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WO2024263790A2 - Nouveau co-médicament, co-administration et administration successive d'un antagoniste sélectif du rbp4 et du c20-d3-rétinol pour l'élimination des effets indésirables oculaires basés sur le mécanisme dans le traitement de la dégénérescence maculaire, de la stéatose hépatique non alcoolique (nafld) et de l'arthrite goutteuse (goutte) - Google Patents

Nouveau co-médicament, co-administration et administration successive d'un antagoniste sélectif du rbp4 et du c20-d3-rétinol pour l'élimination des effets indésirables oculaires basés sur le mécanisme dans le traitement de la dégénérescence maculaire, de la stéatose hépatique non alcoolique (nafld) et de l'arthrite goutteuse (goutte) Download PDF

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Publication number
WO2024263790A2
WO2024263790A2 PCT/US2024/034834 US2024034834W WO2024263790A2 WO 2024263790 A2 WO2024263790 A2 WO 2024263790A2 US 2024034834 W US2024034834 W US 2024034834W WO 2024263790 A2 WO2024263790 A2 WO 2024263790A2
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compound
selective
alkyl
rbp4
alkylenyl
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WO2024263790A3 (fr
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Konstantin Petrukhin
Christopher L. Cioffi
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Columbia University in the City of New York
Rensselaer Polytechnic Institute
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Columbia University in the City of New York
Rensselaer Polytechnic Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • AMD age-related macular degeneration
  • treatments exist, particularly for the subset known as wet AMD, treatment is still limited for dry AMD to supportive care to delay the onset of the disease where the supportive care relates to the use of AREDS (Age- 35 Related Eye Disease Study) formula of vitamins and nutrients.
  • AREDS Age- 35 Related Eye Disease Study
  • the FDA Food and Drug Administration
  • SYFOVRETM intravitreal pegcetacoplan
  • Apellis Pharmaceuticals, Inc. for treating geographic atrophy (GA) secondary to dry AMD
  • the treatment is based on a pegylated peptide that is a complement inhibitor.
  • 40 pegcetacoplan binds to complement protein C3 and its activation 4877-4589-0155v.1 2 fragment C3b with high affinity, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation.
  • the treatment is also associated with inconvenient intraocular delivery, and its efficacy is not optimal.
  • Oral therapies, 5 such as co-drug therapies, will have a significant advantage over pegcetacoplan in terms of patient convenience. They further have a mechanism that is independent of direct modulation of the complement cascade in the retina.
  • An attractive target for treatment of the disease is the downregulation of serum retinol, but current approaches 10 cause adverse events in patients, limiting their usage.
  • Photoreceptor loss in dry AMD is secondary to abnormalities in the Retinal Pigment Epithelium (RPE), a cellular layer that provides critical metabolic support to rods and cones.
  • RPE Retinal Pigment Epithelium
  • Age-dependent 15 accumulation of lipofuscin in the RPE is associated with age-related increased incidences of dry AMD and may be one of several pathogenic factors contributing to disease onset and progression.
  • Bisretinoids which are byproducts of the visual cycle stemming from retinaldehyde dimerization, mediate lipofuscin toxicity and exert a variety of 20 deleterious effects on RPE cells (Bergmann, M. et al. 2004; Sparrow, J.R. et al. 2003; Dorey, C.K. et al.
  • enhanced bisretinoid 30 biosynthesis represents the sole causative factor underlying Stargardt disease (STGD1), a genetic form of macular degeneration (Birnbach, C.D. et al. 1994; De Laey, J.J. & Verougstraete, C. 1995; Delori, F.C. 1995; Eagle, R.C. et al. 1980).
  • STGD1 Stargardt disease
  • the non-enzymatic biosynthesis of cytotoxic bisretinoids involves two condensations of all-trans- 35 retinaldehyde (Sparrow, J.R. et al.
  • Serum retinol is delivered to the retina from circulation in a tertiary complex with Retinol-Binding Protein 4 (RBP4) and transthyretin (TTR). Without interacting with TTR, holo- 10 RBP4 is rapidly cleared via glomerular filtration.
  • RBP4 Retinol-Binding Protein 4
  • TTR transthyretin
  • RBP4-TTR interaction is retinol-dependent
  • compounds antagonizing retinol binding to RBP4 may also induce dissociation of the RBP4-TTR complex with a subsequent reduction in circulating levels of retinol and RBP4.
  • Selective RBP4 antagonists are highly effective in lowering serum RBP4 and reducing bisretinoid synthesis in relevant mouse models.
  • human clinical use of selective RBP4 antagonists may be associated with mechanism-based ocular adverse effects (AEs), even though no 20 ocular adverse effects were induced in mice, as previously reported (Dobri, N. et al. 2013; Racz, B. et al. 2018).
  • fenretinide a prototypical RBP4 antagonist
  • transient and reversible ocular AEs such as diminished dark adaptation, in a subset 25 of patients (yearly prevalence: 5.8-6.7%) (Camerini, T. et al. 2001).
  • a Phase 2 fenretinide trial in patients with dry AMD reported reversible reduction in dark adaptation in ⁇ 10% of drug- treated patients (no ocular AEs with placebo) (Mata, N.L. et al. 2013).
  • Tinlarebant another RBP4 antagonist
  • safety data presented by 30 Belite Bio indicates that a subset of patients may develop asymptomatic delayed dark adaptation (measured only instrumentally) or symptomatic xanthopsia (abnormalities in cone vision).
  • Age-related macular degeneration (AMD) is the leading cause of 35 blindness in developed countries. It is estimated that 62.9 million individuals worldwide currently have the most prevalent atrophic (dry) form of AMD; 8 million of them are Americans. Due to increasing life 4877-4589-0155v.1 4 expectancy and current demographics, this number is expected to significantly increase in the future.
  • Non-alcoholic fatty liver disease encompasses a spectrum of 10 conditions associated with lipid deposition in hepatocytes of the liver. Hepatic steatosis refers to accumulation of lipids in the liver. NAFLD is characterized by hepatic steatosis due to causes other than excessive alcohol use.
  • hepatic steatosis is defined as a hepatic triglyceride content that exceeds 5% of total liver 15 weight. While simple hepatic steatosis is on the least extreme side of the NAFLD spectrum, it can progress to more severe conditions of the NAFLD spectrum such as mild hepatic steatosis and non-alcoholic steatohepatitis (NASH). NASH is the extreme form of NAFLD which is characterized by lipid accumulation in the liver combined with 20 inflammation and hepatocellular injury or fibrosis. NASH frequently leads to severe liver complications such as cirrhosis and hepatocellular carcinoma.
  • NAFLD is the most common form of chronic liver disease in the United 25 States, affecting an estimated 75 to 100 million people. There is no currently approved pharmacotherapy for any form of NAFLD. Developing a drug therapy for NAFLD is of extreme importance.
  • C. Gouty arthritis (gout) 30 Gouty arthritis (gout) is the most common form of inflammatory arthritis and affects more than 8 million people in the Unites States.
  • Uric acid is a metabolic product resulting from the metabolism of purines, which are found in many foods and in human tissue. Gout is caused by excess uric acid levels in the blood, which lead to the 35 deposition of monosodium urate crystals in tissue.
  • Risk factors 4877-4589-0155v.1 5 for gout include being overweight or obese, having hypertension, alcohol intake, diuretic use, a diet rich in meat and seafood, excessive consumption of fructose, and poor kidney function. 5 Acute flares occur when urate crystals in the joint cause acute inflammation. A flare is characterized by pain, redness, swelling, and warmth lasting days to weeks. Pain may be mild or excruciating. Most initial attacks occur in lower extremities. The typical presentation in the metatarsophalageal joint of the great toe 10 (podagra) is the presenting joint for 50% of people with gout.
  • Chronic gout is characterized by chronic arthritis, with soreness and aching of joints. People with gout may also get tophi or lumps of urate crystals deposited in soft tissue. Clinically inactive (intercritical) segments between gout flares occur after an acute flare has subsided. 15 A person with gout continues to have hyperuricemia, which results in continued deposition of urate crystals in tissues and resulting damage. Intercritical segments become shorter as the disease progresses. 20 Uric acid is synthesized from its precursor, xanthine, by an enzyme called xanthine oxidase (XO). Accordingly, XO inhibitors (e.g., allopurinol and febuxostat) dominate the market.
  • XO inhibitors e.g., allopurinol and febuxostat
  • Summary of the Invention 5 resent disclosure provides two-component co-drug, co- administration, and sequential-administration strategies that combine the ability to reduce retinol while simultaneously mitigating the adverse events associated with loss of retinol.
  • the co-drug as a10 representative example, is formed from the conjugation of a RBP4- lowering compound with a deuterated retinol.
  • the first component treats the disease by limiting delivery of retinol while the second component (“C20-D3-visual-chromophore- producing compound”) suppresses production of additional lipofuscin 15 bisretinoid and reduces the adverse effects associated with partial reduction in production of the visual chromophore, 11-cis- retinaldehyde, in the retina.
  • the present disclosure provides means to overcome the toxicity associated with current macular degeneration treatments while still maintaining the pharmacological 20 effects.
  • the first component, a “selective RBP4 antagonist,” is a chemical entity that engages the RBP4 of the RBP4-TTR complex, which is involved in delivery of retinol to the retina.
  • the second component a “C20-D3-visual-chromophore-producing compound,” is defined as any C20-D3-modified retinoid or carotenoid that upon metabolism in a mammal can eventually produce a C20-D3 visual chromophore that represents C20-D3-9-cis-retinaldehyde or C20- D3-11-cis-retinaldehyde in the retina.
  • Examples of a C20-D3-visual- 30 chromophore-producing compound include C20-D3-retinol, which is a deuterated form of vitamin A (retinol), C20-D3-retinaldehyde, C20-D3- retinyl esters (such as C20-D3-retinyl acetate), C20-D3-9-cis- retinol, C20-D3-9-cis-retinaldehye, C20-D3-9-cis-retinyl esters (such 4877-4589-0155v.1 10 as C20-D3-9-cis-retinyl acetate), C20-D3-11-cis-retinol, C20-D3-11- cis-retinaldehye, C20-D3-11-cis-retinyl esters (such as C20-D3-11- cis-retinyl acetate), and C20-D
  • the deuteration at the C20 position reduces the formation of lipofuscin bisretinoid 5 while other functions (such as providing a precursor for in vivo synthesis of the visual chromophore, 11-cis-retinaldehyde) are not reduced. Additional deuterations at positions other than C20 are possible.
  • the C20-D3-visual-chromophore- producing compound When absorbed in the body of a mammal, the C20-D3-visual-chromophore- producing compound initially generates C20-D3-retinol in a form of one of three stereoisomers: C20-D3-all-trans-retinol, C20-D3-9-cis- retinol, and C20-D3-11-cis retinol.
  • deuterated all-trans-retinol undergoes isomerization by retinoid 15 isomerohydrolase RPE65 to form 11-cis-retinol which in turn is converted to 11-cis-retinaldehyde, a visual chromophore.
  • retinoid 15 isomerohydrolase RPE65 Upon delivery to the retina, deuterated all-trans-retinol undergoes isomerization by retinoid 15 isomerohydrolase RPE65 to form 11-cis-retinol which in turn is converted to 11-cis-retinaldehyde, a visual chromophore.
  • cis retinoids can directly produce the visual chromophore without requiring this isomerization reaction.
  • the visual chromophore can be either 11-cis-retinaldehyde (a natural chromophore) or 9-cis- 20 retinaldehyde (an artificial chromophore that can bind to opsin and form rhodopsin similarly to 11-cis-retinaldehyde).
  • Various ratios of the first component to the second component may be used.
  • the ratio may be a 1:1 conjugate in its simplest 25 form.
  • the co-drug may be designed following general conjugating approaches developed for the antibody-drug conjugate (ADC) system.
  • the co-drug of the present disclosure is designed to degrade and release the first and second components in the gastrointestinal (GI) tract, or via hydrolysis in blood or 30 lymphatic circulation, not in the target cell as is typical for ADC.
  • the co-drug of the present disclosure is designed to be used orally, while ADC therapies need to be administered by non-oral routes (such as intravenously or subcutaneously).
  • the first component selective RBP4 antagonist
  • C20-D3-visual- 4877-4589-0155v.1 11 chromophore-producing compound the fate of the released C20-D3- retinol will be as follows. It is known that 25-33% of postprandial retinoid-laden chylomicrons are taken by extrahepatic vitamin A- dependent tissues such as the retina (Vogel, S. et al. 2002). Like 5 dietary retinoids, C20-D3-retinol will be esterified in the GI tract, packaged in chylomicrons, and delivered to the retina.
  • Consistent chylomicron delivery of C20-D3-retinoids to the retina will provide a reliable supply of retinoids for the synthesis of visual chromophore (11-cis-retinal) and rhodopsin in visual cycle reactions (Charbel, 10 I.P. et al. 2015), thus partially compensating for the blocking of the RBP4-mediated route and reducing related ocular AEs.
  • C20-D3-retinoids will not contribute to the biosynthesis of bisretinoids due to a kinetic isotope effect that slows bisretinoid synthesis (Charbel, I.P. et al. 2015; Kaufman, Y. et al. 2011; Ma, L. 15 et al.
  • Rhodopsin represents a protein called opsin conjugated with the visual chromophore called 11-cis-retinaldehyde; 9-cis- retinaldehyde can also serve as a visual chromophore in place of 11- cis-retinaldehyde.
  • opsin conjugated with the visual chromophore called 11-cis-retinaldehyde
  • 9-cis- retinaldehyde can also serve as a visual chromophore in place of 11- cis-retinaldehyde.
  • cone opsins blue, red, and green opsins
  • cone20 photoreceptors blue, red, and green cones
  • the co-drug, co- administration, and sequential administration of the present disclosure provide visual chromophores to supplement all four types of functional opsins (rhodopsin, blue-opsin, green-opsin, and red- opsin).
  • the first and second components may also be co-administered as separate chemical entities simultaneously, contemporaneously, or concomitantly (that is, without being conjugated or bonded to each other), or they may be administered sequentially in a suitable order 30 in which the first component is administered first or the second component is administered first.
  • the second component C20-D3-visual-chromophore-producing compound
  • Tinlarebant is shown as the selective RBP4 antagonist.
  • C Examples of co-drugs whereby C20-D3-retinol is linked to the cores via various low-pH and/or proteolytic cleavable linkers that are successfully used 5 in ADC development.
  • the selective RBP4 antagonists are linked via labile esters.
  • connection point (a hemiaminal-type linker) is unstable at low pH, and the co-drug will degrade in the stomach to 15 release tinlarebant and C20-D3-all-trans-retinol.
  • connection point (a carbamate linker) is labile at low pH and in the presence of esterase and/or protease (such as lipase).
  • Figure 9 Structure of bisretinoids A2E and isoA2E, cytotoxic 20 components of retinal lipofuscin.
  • Connection point in A is unstable at 30 low pH; should degrade in the stomach to release tinlarebant and C20D3-all-trans-retinol.
  • Connection point (carbamate) in B is also predicted to be labile in the presences of esterases and proteases.
  • Figure 12. Proposed Tinlarebant-C20D3-all-trans-Retinol Co-Drug A. Connection point in A is unstable at low pH; it should degrade in the 35 stomach to release tinlarebant and C20D3-all-trans-retinol. 4877-4589-0155v.1 14 Figure 13.
  • Figure 21 Proposed BPN-14634-C20D3-all-trans-Retinol Co-Drug B.
  • Figure 22 Proposed BPN-14634-C20D3-all-trans-Retinol Co-Drug B. Tether based on nucleotide prodrug strategy.
  • BPN-14634 can be liberated either via direct hydrolysis of the methylene linker or via degradation of the linker after carbamate hydrolysis (carbamate 35 pathway). 4877-4589-0155v.1 15 Figure 23.
  • BPN-14634 can be liberated either via direct hydrolysis of the methylene linker or via degradation of the linker after ester hydrolysis (similar to the 5 carbamate pathway shown in Figure 22).
  • Figure 24 Effect of ⁇ -carotene on rhodopsin levels in ACPHS-14- treated Balb/c mice. 10
  • Figure 25 Effect of ⁇ -carotene on scotopic ERG a-wave amplitude elicited at the 1.89 log cd*s/m2 light intensity in ACPHS-14-treated Balb/c mice.
  • Figure 26 Effect of ⁇ -carotene on scotopic ERG a-wave amplitude elicited at the 1.89 log cd*s/m2 light intensity in ACPHS-14-treated Balb/c mice.
  • Treated mice were given 7 daily oral dose of 25 mg/kg ACPHS-52 or the same dose of ACPHS-52 along with 3.3 mg/kg C20-D3-retinyl acetate. Untreated control mice were kept on standard diet.
  • vitamin A, 1 ( Figure 1) serves as a precursor for the biosynthesis of retinoic acid (2) (Steinmetz, A.C. 4877-4589-0155v.1 16 et al. 2001; Clagett-Dame, M. & DeLuca, H.F. 2002; Wolf, G. 1984), 11-cis-retinal (3) (Kiser, P.D. et al. 2014; Tsin, A. et al. 2018), and many other key retinoids involved in multiple cellular processes and numerous critical biological functions throughout the body.
  • Bisretinoid synthesis in the eye depends on the influx of all-trans- retinol (1) from the serum to the retina. Formation of the tertiary retinol-binding protein 4 (RBP4)–transthyretin (TTR)–retinol complex in the serum is required for this influx. Reducing circulating levels of RBP4 and 1 via selective antagonists could modulate the visual 10 cycle, reduce the rate of cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), and halt geographic atrophy in patients with atrophic (dry) age-related macular degeneration (AMD) and Stargardt disease (Radu, R.A. et al. 2005; Palczewski, K.
  • non-retinoid RBP4 antagonist A1120 (6) (Motani, A. et al. 2009) 4877-4589-0155v.1 17 was found to lower circulating RBP4 plasma levels in rodents by >70% and reduce retinal bisretinoid accumulation in Abca4 -/- mice (Dobri, N. et al. 2013).
  • Selective and orally bioavailable non-retinoid RBP4 antagonists 7 (Cioffi, C.L. et al. 2014) and BPN-14136 (8) (Cioffi, 5 C.L. et al.
  • RBP4 has also been identified as an adipokine, and epidemiological evidence suggests that moderately elevated levels of the protein positively correlate with type 2 diabetes (Graham, T.E. et al. 2006; Yang, Q. et al. 2005), 20 obesity (Aeberli, I. et al. 2007), insulin resistance (Kowalska, I. et al. 2008), cardiovascular disease (Ingelsson, E. et al. 2009; Qi, Q. et al. 2007; Norseen, J. et al. 2012), and hepatic steatosis (Lee, S.A. et al. 2016).
  • RBP4 antagonist 10 significantly lowered serum RBP4 levels in rodents (>80%), reduced the concentration of circulating RBP4 produced in the adipose tissue, and demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that it may 30 have therapeutic utility for the treatment of non-alcoholic fatty liver disease (NAFLD) (Cioffi, C.L. et al. 2019).
  • NAFLD non-alcoholic fatty liver disease
  • tinlarebant also known by 10 the designated codes of “BPN-14697” and “LBS-008”
  • TGD1 TGD1 (Belite Bio 2020)
  • Belite Bio reported positive results from a Phase 1b trial and 6-month interim safety and efficacy data for an ongoing two-year Phase 2 trial 5 involving early-onset STGD1 adolescents chronically dosed with tinlarebant, and a Phase 3 trial with adolescent STGD1 patients has been initiated.
  • this class of compounds does not address the issue of potential mechanism-based ocular AEs associated with serum RBP4 reduction. 10 2.
  • a critical step in bisretinoid synthesis is spontaneous dimerization of retinaldehydes conjugated to phosphatidylethanolamine (PE) via Schiff base formation in photoreceptor membranes (Washington, I. et 15 al. 2016).
  • a rate-determining step in retinaldehyde dimerization is the cleavage of carbon-hydrogen bonds at C20 of the retinaldehyde-PE Schiff base via a [1,6]-hydride shift (Kaufman, Y. et al. 2011).
  • Deuterated retinoids have been used in humans for decades as traces 20 in studies of vitamin A metabolism (Haskell, M.J. et al. 1999; Haskell, M.J.
  • Figures 3 through 6 show, respectively, how C20- D3-retinol, C20-D3-retinyl acetate, C20-D3-9-cis-retinol, C20-D3-11- cis-retinol, and C20-D3-C20’-D3- ⁇ -carotene may be synthesized.
  • Introduction of deuterium at C20 of vitamin A results in a kinetic 25 isotope effect that slows the formation of retinaldehyde dimers in vivo and in vitro (Kaufman, Y. et al. 2011; Ma, L. et al. 2011).
  • C20-D3-retinaldehyde formed dimers 12-times less rapidly than unlabeled retinaldehyde, while bisretinoid A2E formation was reduced by 7-fold (Kaufman, Y. et al. 2011).
  • C20-D3-retinyl acetate was effective in inhibiting bisretinoid synthesis and 5 normalization of complement system dysregulation in the retina of Abca4 -/- mice, a model of Stargardt disease (STGD1) (Charbel, I.P. et al. 2015).
  • ADC Antibody-drug conjugate
  • ADC is a class of therapeutics that combines the selectivity of monoclonal antibodies (mAbs) with the potency of cytotoxic drugs. It is designed to target specific cells, such as cancer cells, while minimizing the impact on healthy cells, thereby enhancing the efficacy and reducing the side effects of 25 traditional chemotherapy (Su, Z. et al. 2021; Alas, M. et al. 2021; Tsuchikama, K. & An, Z. 2018).
  • the structure of an ADC typically consists of three main components: 30 Monoclonal Antibody (mAb): The mAb used in an ADC is designed to recognize and bind to a specific antigen that is overexpressed or selectively present on the target cells, such as tumor cells. The antibody provides the specificity and targeting capability of the ADC. 35 Linker: The linker serves as a bridge between the mAb and the cytotoxic drug. It is engineered to be stable in circulation but capable of releasing the drug payload selectively inside the target 4877-4589-0155v.1 21 cells. The linker plays a crucial role in determining the release kinetics and stability of the ADC.
  • mAb Monoclonal Antibody
  • Cytotoxic Drug Payload The cytotoxic drug, also known as the 5 payload, is the pharmacologically active component of the ADC that exerts a toxic effect on the target cells.
  • the drug is conjugated to the mAb via the linker.
  • the choice of the cytotoxic drug depends on the therapeutic target and desired mechanism of action. 10
  • the mechanism of action of an ADC involves a series of steps: Target Binding: The ADC is administered systemically, and the mAb component recognizes and binds specifically to the target antigen present on the surface of the cancer cells. 15 Internalization: Once the ADC binds to the target cells, it is internalized through receptor-mediated endocytosis, forming an endosome within the cell.
  • the linker Within the endosome, the linker is designed to be cleaved in response to specific conditions present in the target cell’s environment, such as low pH or enzymatic activity. This cleavage releases the cytotoxic drug payload from the ADC.
  • Cytotoxic Effect After release, the cytotoxic drug enters the cytoplasm or other cellular compartments, where it exerts its toxic effect. The drug may disrupt cellular processes, inhibit DNA replication, promote apoptosis (programmed cell death), or interfere with microtubule formation, depending on the specific drug used.
  • the goal of ADC therapy is to deliver the cytotoxic drug specifically to the target cells, reducing off-target effects and minimizing damage to healthy tissues.
  • ADCs offer the potential for improved 35 therapeutic efficacy with reduced systemic toxicity compared to conventional chemotherapy. 4877-4589-0155v.1 22
  • the co-drug designs of the present disclosure take advantage of a wide variety of established linkers used in antibody-drug conjugate (ADC) systems for rapid payload release via acidic pH or proteolytic cleavage (Su, Z. et al. 2021; Alas, M. et al. 2021; Tsuchikama, K. & 5 An, Z. 2018).
  • a co-drug containing C20-D3-retinol linked to its core via a low-pH sensitive carbonate, silyl ether, or ester linker will rapidly cleave in the stomach and upper GI tract, readily releasing C20-D3-retinol for intestinal absorption and chylomicron packaging.
  • Selective RBP4 antagonists of the co-drugs may be attached 10 to their respective cores via ester, carbamate, or hemiaminal linkages, which will undergo rapid chemical and enzymatic hydrolysis in the GI tract.
  • Figure 7 describes key design principles of the co-drug platform of 15 the present disclosure, using tinlarebant (BPN-14697; LBS-008) as an example of a selective RBP4 antagonist.
  • BPN-14697 tinlarebant
  • LBS-008 tinlarebant
  • the present invention provides a proposed Tinlarebant-C20D3-all-trans-Retinol Co-Drug A having the following structure: 4877-4589-0155v.1 23 . escribed in Figure 12.
  • the connection point in A is unstable at low pH; and should degrade in the stomach to release tinlarebant and C20D3-all-trans-retinol. (See 5 Figure 13). (Heterocycles (1986), 24(8), 2233-7; Pharmazie (1980), 35(12), 746-8; WO2021113436; and WO2002041835).
  • Proposed Tinlarebant-C20D3-all-trans-Retinol Co-Drug B The present invention provides a proposed Tinlarebant-C20D3-all- 10 trans-Retinol Co-Drug B having the following structure: .
  • the proposed synthesis steps are described in Figure 14.
  • the connection point (cabamate) in B is predicted to be labile in the presences of esterases and proteases. (Croatica Chemica Acta (2003), 15 76(3), 217-228).
  • Proposed Tinlarebant-C20D3-all-trans-Retinol Co-Drug C The present invention provides a proposed Tinlarebant-C20D3-all- trans-Retinol Co-Drug C having the following structure: 4877-4589-0155v.1 24 .
  • the proposed synthesis steps are described in Figure 15.
  • the long alkyl chain tether serves as a fatty acid mimic and should be labile to pancreatic lipases in the small intestines.
  • Various R groups are 5 shown in Figure 16. Pepsin cleaves preferentially after phenylalanine, tyrosine, and tryptophan.
  • R groups recognized by pepsin and/or chymotrypsin could also enable degradation in the stomach and/or small intestines.
  • the ester in Co-Drug C is labile to hydrolysis especially at low pH in the stomach and is labile to esterases and lipases in 10 the small intestines.
  • Proposed Tinlarebant-C20D3-all-trans-Retinol Co-Drug D The present invention provides a proposed Tinlarebant-C20D3-all- trans-Retinol Co-Drug D having the following structure ( Figures 17 15 and 18): . T e s y e e s a e o y o ys s a o p e stomach.
  • Proposed BPN-14634-C20D3-all-trans-Retinol Co-Drugs 20 The present invention provides proposed BPN-14634-C20D3-all-trans- Retinol Co-Drugs A, B, and C. (See Figure 19). (Chemical Papers (1985), 39(3), 413-27). 4877-4589-0155v.1 25 Proposed BPN-14634-C20D3-all-trans-Retinol Co-Drug A
  • the present invention provides a proposed BPN-14634-C20D3-all-trans- Retinol Co-Drug A having the following structure: 5 .
  • the proposed synthesis steps were described in Figure 20. (CN 101671369; and CN105001193).
  • Co-Drug C is tether based on nucleotide prodrug strategy and BPN-14634 can be liberated either via direct hydrolysis of the methylene linker or via degradation of the linker after ester hydrolysis (similar to 5 carbamate pathway of Co-Drug B). ( Figure 23).
  • One embodiment of the present disclosure is a co-drug that: contains an optimal molar ratio of a selective RBP4 antagonist to C20-D3- retinol (e.g., within a 1:1 to 5:1 range or within a 1:1 to 1:5 range); 10 and can readily degrade to liberate the selective RBP4 antagonist and the C20-D3-retinol in the GI tract for chylomicron packaging and delivery.
  • a wide variety of established linkers used in antibody-drug conjugate (ADC) systems for rapid payload release via acidic pH or proteolytic cleavage may be used for this purpose (Su, Z. et al. 2021; 15 Alas, M. et al. 2021; Tsuchikama, K.
  • a co-drug containing C20-D3-retinol linked to a core via a carbonate or silyl ether linker can rapidly cleave in the stomach and upper GI tract, readily releasing C20-D3-retinol for intestinal absorption and chylomicron packaging.
  • the selective RBP4 antagonists of the co-drugs 20 can be attached to their respective cores via ester, carbamate, or 4877-4589-0155v.1 27 hemiaminal linkages, which will undergo rapid chemo- and enzymatic hydrolysis in the GI tract.
  • a selective RBP4 antagonist and a C20-D3-visual-chromophore-producing 15 compound may also be chemically bonded directly to each other to form a co-drug, namely, without involving an intervening linker.
  • “bisretinoid lipofuscin” is lipofuscin containing a cytotoxic bisretinoid. Cytotoxic bisretinoids include but are not 20 necessarily limited to A2E, isoA2E, atRAL di-PE (all-trans-retinal dimer-phosphatidylethanolamine), and A2-DHP-PE (A2-dihydropyridine- phosphatidylethanolamine) ( Figures 9 and 10).
  • Bisretinoid-mediated macular degeneration may comprise the accumulation of lipofuscin deposits in the retinal pigment epithelium.
  • “combination” means an assemblage of reagents for use in therapy either by simultaneous or contemporaneous administration.
  • Simultaneous administration refers to administration of an admixture (whether a true mixture, a suspension, an emulsion, or other physical 30 combination) of the first compound and the second compound.
  • the combination may be the admixture or separate containers of the first compound and the second compound that are combined just prior to administration.
  • Contemporaneous administration refers to the separate administration of the first compound and the second compound 35 at the same time, or at times sufficiently close together that an additive or preferably synergistic activity relative to the activity of either the first compound or the second compound alone is observed. 4877-4589-0155v.1 28
  • “concomitant administration” or “administering concomitantly” means the administration of two agents given in close enough temporal proximity to allow the individual therapeutic effects 5 of each agent to overlap.
  • additive-on or “add-on therapy” means an assemblage of reagents for use in therapy, wherein the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to 10 beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time.
  • the present disclosure provides a compound having the general 15 structure (P-) a M(-Q) b or P(-Q) b , wherein: P represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom or by eliminating a hydroxyl group from a selective RBP4 antagonist; a is 1, 2, 3, 4, or 5; 20 Q represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom or by eliminating a hydroxyl group from a C20-D3-visual-chromophore-producing compound; b is 1, 2, 3, 4, or 5; M represents an (a+b)-valence group comprising carbon, hydrogen, 25 nitrogen, and oxygen atoms; each P in (P-) a M(-Q) b is independently bonded to M via an ester, carbonyl, peptide, carbamate, or hemiaminal linkage that is cleavable at an acidic pH or is enzymatically cleavable; each
  • the present disclosure provides a compound having the general 30 structure (P-) a M(-Q) b or P(-Q) b , wherein: P represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom or by eliminating a hydroxyl group from a selective RBP4 antagonist; 4877-4589-0155v.1 32 a is 1, 2, 3, 4, or 5; Q represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom or by eliminating a hydroxyl group from a C20-D3-visual-chromophore-producing compound; 5 b is 1, 2, 3, 4, or 5; M represents an (a+b)-valence group comprising carbon, hydrogen, and oxygen atoms; each P in (P-) a M(-Q) b is independently bonded to M via an ester, carbamate, or hemiaminal linkage that is cleavable at an acidic pH or 10 is enzymatically cleavable;
  • the selective RPB4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , 20 or C 1 -C 4 alkyl. In some embodiments, the selective RPB4 antagonist is the compound R 6 wherein L is B. 4877-4589-0155v.1 36 In some embodiments, the selective RBP4 antagonist is the compound R 6 wherein L is B'.
  • the selective RBP4 antagonist is the compound 5 wherein R 6 , R 1 , R 2 , R 3 , R 4 , and R 5 are other than H, and when 10 R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R1 is CF3, R2is H, R3 is F, R4 is H, and R5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or 15 R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, CH 3 N O then B is other tha .
  • the selective RBP4 antagonist is the compound N 1. In some embodiments, the selective RBP4 antagonist is the compound 5 wherein , r present, and when present, is H, OH, or halogen, and 10 when ⁇ is present, then R 6 is absent, and when ⁇ is absent, then R 6 is present. In some embodiments, the selective RBP4 antagonist is the compound wherein 1 . 15 4877-4589-0155v.1 38 In some embodiments, the selective RBP4 antagonist is the compound X 2. In some embodiments, the selective RBP4 antagonist is the compound 5 wherein R 6 , , . 10 In some embodiments, the selective RBP4 antagonist is the compound wherein 2 .
  • the selective RBP4 antagonist is 4877-4589-0155v.1 39 O , O , , , 4877-4589-0155v.1 40 CF CF , , , , 4877-4589-0155v.1 41 , , O , O , 4877-4589-0155v.1 42 , , , 4877-4589-0155v.1 43 CF 3 CF 3 CF 3 O O N O N O N O N O N O 4877 44 O , CF 3 , CH 3 , CH 3 , 4877-4589-0155v.1 45 CH 3 , CH 3 , C F 3 , , 4877-4589-0155v.1 46 H 3 , 3 ) 2 , O , NH 4877-4589-0155v.1 47 , O O , 4877-4589-0155v.1 48 O , S O2 , , 4877-4589-0155v.1 49 CF 3 CF 3
  • the selective RBP4 antagonist is C H 3 OH 5 , H 2 , 4877-4589-0155v.1 86 F F C F 3 CF 3 CF 3 CF 3 OH , 5
  • the selective RBP4 antagonist is the compound having the structure R 3 R 3 R 4 R 2 R 3 Y , or a pharma 10
  • the selective RBP4 antagonist is 4877-4589-0155v.1 87 , , or a phar 5
  • P is F F 3 .
  • Q is 4877-4589-0155v.1 88 , , 20.
  • the present invention provides a compound having the following structure: , 4877-4589-0155v.1 89 , , 4877-4589-0155v.1 90 , , 5 , 4877-4589-0155v.1 91 , wherein n is 0-20; R is H, Trp, Phe, Leu, or Tyr; 5 , 4877-4589-0155v.1 92 , e e s .
  • the selective RBP4 antagonist is the compound having the structure: 4877-4589-0155v.1 93 R 3 R 4 R 2 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl; 5 X is N or CR 6 , wherein R 6 is H, OH, or halogen; H A is absent or present, and when present, is ; B has the structure: R 7 R 8 R 9 10 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; 15 X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alky
  • the selective RBP4 antagonist is the compound having the structure R 3 R 3 R 3 R 2 R 1 . 4877-4589-0155v.1 95 In some embodiments, the selective RBP4 antagonist is the compound having the structure R 3 R 3 R 3 R 4 R 2 R 4 R 2 R 1 . 5 In some embodiments, the selective RBP4 antagonist is the compound having the structure R 3 R 3 R 3 R R R R R R 1 .
  • the selective RBP4 antagonist is the compound 10 having the structure: 4877-4589-0155v.1 96 R 3 R 4 R 2 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are ea c ndependently H, halogen, CF 3 , or C 1 -C 4 alkyl; and 5 B has the structure: R 7 R 8 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , 10 wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R7, R8, and R9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O- 15 alkyl, halo
  • the selective RBP4 antagonist is the compound 10 having the structure: R 3 R 4 R 2 Y B , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl; 15 Y is alkyl; H A is absent or present, and when present, ; and B has the structure: R 7 R 8 R 9 20 wherein 4877-4589-0155v.1 98 ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; 5 X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-
  • the selective RBP4 antagonist is the compound having the structure 4877-4589-0155v.1 99 R 3 R 3 R 4 R 2 R 3 R 4 R 2 R 4 R 2 1 Y .
  • the selective RBP4 antagonist is the compound wherein B has the structure: R 7 R 8 5 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; 10 X 2 is C or N; X 3 is CH or N; and R7, R8, and R9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O(CO)- alkyl, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, cycloalkyl
  • the selective RBP4 antagonist is the compound 25 wherein B or B 2 has the structure 4877-4589-0155v.1 100 R 11 N R N 12 13 wherein R 11 , R 12 , and R 13 are eac p y , halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O(CO)- 5 alkyl, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)-NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R N 8 10 R 9 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- 15 NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 8 R 9 20 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH2, C(O)-N(CH3)2, C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure 4877-4589-0155v.1 wherein R7, R8, and R9 are each indep , halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure: R 7 R 8 R 9 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 ; and R 10 is alkyl, alkenyl, or alkynyl.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 2 CH 3 , C(O)OH, or C(O)-NH 2.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, halogen, or alkyl. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 7 , R 8 , and R 9 are each H and the remaining one of R 7 , R 8 , and R 9 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 7 , R 8 , and R 9 is H and the remaining two of R 7 , R 8 , and R 9 are each other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 8 R 9 .
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 9 .
  • the selective RBP4 antagonist is the compound wherein R 7 and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R9 .
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 9 .
  • the selective RBP4 antagonist is the compound wherein R 7 and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B has the structure R 7 R 8 R9 .
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein R 7 and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 8 R 9 .
  • the selective RBP4 antagonist is the compound wherein: R 7 , R 8 , and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br; and R 10 is alkyl.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 9 .
  • the selective RBP4 antagonist is the compound wherein: R 7 and R 9 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br; and R 10 is alkyl.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 11 N R N 12 13 wherein R 11 , R 12 , and R 13 endently H, halogen, alkyl, alkylenyl-OH, alkylenyl 2 , y yl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)- N(CH 3 ) 2 , C(O)-NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 2 CH 3 , C(O)OH, or C(O)-NH 2 .
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, halogen, or alkyl. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 11 , R 12 , and R 13 are each H and the remaining one of R 11 , R 12 , and R 13 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 11 , R 12 , and R 13 is H and the remaining two of R 11 , R 12 , and R 13 are each other than H.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 11 N
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 11 N N 1 3 .
  • the selective RBP4 antagonist is the compound wherein R 11 and R 13 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein X is N.
  • the selective RBP4 antagonist is the compound wherein X is CH.
  • the selective RBP4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each H, t-Bu, Cl, F, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 or t-Bu. In some embodiments, the selective RBP4 antagonist is the compound wherein: R 1 , R 3 , and R 4 are each H; R 2 is halogen; and R 5 is CF 3 or t-Bu. In some embodiments, the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 or t-Bu.
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 . In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two or more of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H.
  • the selective RBP4 antagonist is the compound wherein three of R1, R2, R3, R4, and R5are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein three or more of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is
  • the selective RBP4 antagonist is the compound N wherein B or B 2 is other than .
  • the selective RBP4 antagonist is the compound having the structure: R 3 2 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, alkyl, haloalkyl, O-haloalkyl, aryl, or heteroaryl;
  • X is N or CR 6 , wherein R 6 is H, OH, or halogen;
  • NH A is absent or present, and when present, ; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent;
  • X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl;
  • X 2 is C or N;
  • X 3 is CH or N;
  • R 7 , R 8 , and R 9 are each independently H, halogen, al
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 R 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is , NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O- alkyl, haloalkyl, cycloalkyl, cyclo
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 Y B , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; Y is alkyl; O NH A is absent or present, and when present, is ; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alky
  • the selective RBP4 antagonist is the compound wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each H, methyl, ethyl, phenyl, t-Bu, i-Pr, OCF 3 , CF 3 , OCF 2 CF 3 , CF 2 CF 3 , Cl, Br, or F.
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is -H, OCF 3 , CF 2 CF 3 , methyl, ethyl, i-Pr, or phenyl. In some embodiments, the selective RPB4 antagonist is
  • a is 2 and b is 1. In some embodiments, a is 1 and b is 1. In some embodiments, a is 2, b is 1, and M is , wherein x is 1, 4, or 5. In some embodiments, a is 2, b is 1, and M is , wherein x is 1, 2 4, or 5. In some embodiments, a is 2, b is 1, and M is 5.
  • a is 1, b is 1, and M is , wherein x is 1, In some embodiments, a is 1, b is 1, and M is , wherein x is 1, In some embodiments, a is 1, b is 1, and M is , wherein x is 0, 1, 2
  • the present disclosure provides a pharmaceutical composition comprising the compound (P-)aM(-Q)bor P(-Q)bof the present disclosure and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method for treating a disease characterized by excessive or age-related lipofuscin accumulation in the retina in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the compound of the present disclosure or an effective amount of the pharmaceutical composition of the present disclosure.
  • the disease is further characterized by bisretinoid-mediated macular degeneration.
  • the amount of the compound is effective to lower the serum concentration of RBP4 in the mammal, or the amount of the compound is effective to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal.
  • the bisretinoid is A2E. In some embodiments of the method, the bisretinoid is isoA2E. In some embodiments of the method, the bisretinoid is A2-DHP-PE. In some embodiments of the method, the bisretinoid is atRAL di-PE. In some embodiments of the method, the disease characterized by age- related lipofuscin accumulation in the retina is Age-Related Macular Degeneration. In some embodiments of the method, the disease characterized by age- related lipofuscin accumulation in the retina is dry (atrophic) Age- Related Macular Degeneration. In some embodiments of the method, the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease.
  • the disease characterized by excessive lipofuscin accumulation in the retina is other forms of retinopathy caused by or associated with mutations in the ABCA4 gene, such as retinitis pigmentosa (RP19) or cone-rod dystrophy (CORD3).
  • the disease characterized by excessive lipofuscin accumulation in the retina is Best disease.
  • the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy.
  • the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt-like macular dystrophy.
  • the administration is effective to reduce photoreceptor degeneration.
  • the bisretinoid-mediated macular degeneration is Age-Related Macular Degeneration or Stargardt Disease. In some embodiments of the method, the bisretinoid-mediated macular degeneration is Age-Related Macular Degeneration. In some embodiments of the method, the bisretinoid-mediated macular degeneration is dry (atrophic) Age-Related Macular Degeneration. In some embodiments of the method, the bisretinoid-mediated macular degeneration is Stargardt Disease.
  • the bisretinoid-mediated macular degeneration is other forms of retinopathy caused by or associated with mutations in the ABCA4 gene, such as retinitis pigmentosa (RP19) or cone-rod dystrophy (CORD3).
  • the bisretinoid-mediated macular degeneration is Best disease.
  • the bisretinoid-mediated macular degeneration is adult vitelliform maculopathy.
  • the bisretinoid-mediated macular degeneration is Stargardt-like macular dystrophy.
  • the compound of the present disclosure upon hydrolysis and/or proteolytic cleavage, exhibits retinol-binding protein 4 (RBP4) antagonist activity as well as activity of promoting rhodopsin and cone opsins production. In some embodiments, the compound of the present disclosure, upon hydrolysis and/or proteolytic cleavage, reduces circulating RBP4 levels and promotes rhodopsin and cone opsins production. In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of dry age-related macular degeneration (AMD). In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of type 2 diabetes.
  • AMD dry age-related macular degeneration
  • the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of type 2 diabetes.
  • the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of obesity. In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of insulin resistance. In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of cardiovascular disease. In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of hepatic steatosis. In some embodiments, the compound of the present disclosure or the pharmaceutical composition of the present disclosure may be used for the treatment of non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides a method for treating a non-alcoholic fatty liver disease (NAFLD) in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the compound of the present disclosure or an effective amount of the pharmaceutical composition of the present disclosure.
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides a method for treating gout in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the compound of the present disclosure or an effective amount of the pharmaceutical composition of the present disclosure.
  • the mammal is afflicted with a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • the method further comprises a step of determining, or having determined, the level of RBP4 in adipose tissue in the mammal and administering to the mammal the compound of the present disclosure or the pharmaceutical composition of the present disclosure if the level of RBP4 in adipose tissue is elevated.
  • the method further comprises a step of determining, or having determined, the level of RBP4 in serum in the mammal and administering to the mammal the compound of the present disclosure or the pharmaceutical composition of the present disclosure if the level of RBP4 in serum is elevated.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective in reducing RBP4 levels in adipose tissue in the mammal.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective in reducing RBP4 levels in serum in the mammal. In some embodiments of the method, the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective in reducing uric acid levels in the serum of the mammal.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to normalize the concentration of triglycerides in the liver of the mammal.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to normalize the concentration of free fatty acids in the serum of the mammal.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to normalize the concentration of free fatty acids in the liver of the mammal.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to prevent trafficking of a fatty acid by RBP4.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to prevent trafficking of a fatty acid to the liver by RBP4.
  • the amount of the compound of the present disclosure or the amount of the pharmaceutical composition of the present disclosure is effective to inhibit binding between RBP4 and a fatty acid.
  • the fatty acid is from adipose tissue. In some embodiments of the method, the mammal does not have elevated serum RBP4 levels.
  • the mammal has elevated serum RBP4 levels.
  • the serum RBP4 level of the mammal is elevated by more than 3 micrograms per ml.
  • the NAFLD is a hepatic steatosis selected from simple hepatic steatosis and mild hepatic steatosis.
  • the amount of the compound of the present disclosure administered is such that the amount of the selective RBP4 antagonist released in the body of the mammal is 5- 1000 mg, 5-800 mg, 5-200 mg, 45-200 mg, 45-1000 mg, 45-800 mg, 10- 50 mg, 96 mg, 24 mg, or 10 mg per day.
  • the method further comprises administering an amount of a second agent which is (R)-(+)-(5,6- dichloro 2,3,9,9a-tetrahydro 3-oxo-9a-propyl-lH-fluoren-7- yl)oxy]acetic acid (DPOFA), a Nonsteroidal Anti-inflammatory Drug (NSAID) such as indomethacin, colchicine, lesinurad, corticosteroids (e.g., betamethasone, prednisone, dexamethasone, cortisone, hydrocortisone, methylprednisone, prednisolone), biologic anti-IL- lalpha/beta agents (e.g., canakinumab, rilonacept, anakinra), allopurinol, benzbromarone, pegloticase, and other forms of uricase enzymes, topiroxostat (FYX-051), ulodesine (SID-051),
  • the mammal is afflicted with gout.
  • the amount of the second agent and/or the amount of the compound or the pharmaceutical composition of the present disclosure is effective in reducing uric acid levels in the blood of the mammal.
  • the amount of the second agent and/or the amount of the compound or the pharmaceutical composition of the present disclosure is effective in decreasing uric acid reabsorption in the kidneys of the mammal.
  • the amount of the second agent is effective in increasing uric acid clearance in the mammal.
  • the amount of the second agent is effective in increasing uric acid levels in the urine of the mammal.
  • the amount of the second agent is effective in increasing renal clearance of uric acid in the mammal.
  • the amount of the second agent and/or the amount of the compound or the pharmaceutical composition of the present disclosure is effective in reducing one or more symptoms associated with gout in the mammal.
  • the one or more symptoms associated with gout are selected from joint pain, joint inflammation, joint redness, and decreased range of motion at the joint.
  • the amount of the second agent and/or the amount of the compound or the pharmaceutical composition of the present disclosure is effective in preventing gout in the mammal.
  • the preventing comprises increasing uric acid levels in the urine of the mammal.
  • the preventing comprises reducing uric acid levels in the blood of the mammal.
  • the preventing comprises increasing uric acid clearance in the mammal.
  • the preventing comprises decreasing uric acid reabsorption in the kidneys of the mammal.
  • the preventing comprises increasing renal clearance of uric acid in the mammal.
  • the preventing comprises reducing one or more symptoms associated with gout in the mammal.
  • the one or more symptoms associated with gout are selected from joint pain, joint inflammation, joint redness, and decreased range of motion at the joint.
  • the gout is chronic gout.
  • the gout is acute gout.
  • the amount of the second agent and/or the amount of the compound or the pharmaceutical composition of the present disclosure prevents a recurrence of chronic gout.
  • the mammal is female and the administration of the compound of the present disclosure or the administration of the pharmaceutical composition of the present disclosure reduces the uric acid level to 2.4-6.0 mg/dL.
  • the mammal is male and the administration of the compound of the present disclosure or the administration of the pharmaceutical composition of the present disclosure reduces the uric acid level to 3.4-7.0 mg/dL.
  • the administration of the compound of the present disclosure or the administration of the pharmaceutical composition of the present disclosure reduces uric acid levels in the mammal to less than 7 mg/dL.
  • the compound or the pharmaceutical composition of the present disclosure and the second agent are administered sequentially, simultaneously, contemporaneously, or concomitantly, in which in a sequential administration, the compound or the pharmaceutical composition of the present disclosure may be administered first or the second agent may be administered first.
  • the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure for use in a combination therapy together with a pharmaceutical composition comprising the second agent, for the treatment of a non-alcoholic fatty liver disease (NAFLD) or gout.
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides a pharmaceutical composition comprising an amount of the compound of the present disclosure for use in treating a mammal afflicted with a non-alcoholic fatty liver disease (NAFLD) or gout as an add-on therapy to or in combination with the second agent.
  • NAFLD non-alcoholic fatty liver disease
  • the administration is oral.
  • the mammal is a human.
  • the C20-D3-visual-chromophore-producing compound is selected from the group consisting of C20-D3-retinol, C20-D3-9- cis-retinol, and C20-D3-ll-cis-retinol.
  • the present disclosure provides a pharmaceutical composition
  • a selective RBP4 antagonist is a compound having the structure: R 3 R 2 R 1 wherein L is a lin g g p g he structure H , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; R 6 is H, OH, or halogen, or is absent; ⁇ is absent or present, and when present, is a bond; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro-substituted indole; and the pyrazole
  • the selective RBP4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl.
  • the selective RPB4 antagonist is the compound R 6 wherein B .
  • the selective RBP4 antagonist is the compound R 6 wherein B'.
  • the selective RBP4 antagonist is the compound wherein R 6 , , R 1 , R 2 , R 3 , R 4 , and R 5 are other than H, and R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, CH 3 then B is other
  • the selective RBP4 antagonist is the compound wherein , A , or present, and when present, is H, OH, or , when ⁇ is present, then R 6 is absent, and when ⁇ is absent, then R 6 is present.
  • the selective RBP4 antagonist is the compound O 1.
  • the selective RBP4 antagonist is the compound X 2.
  • the selective RBP4 antagonist is the compound wherein R 6 , , R 6 is H, and . In so me embod ments, the selective RBP4 antagonist is the compound O wherein 2 .
  • the selective RBP4 antagonist is O , O ,
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe 5
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe 5
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe 5
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the selective RBP4 antagonist is the compound having the structure or a pharmaceutically acceptable salt thereof. In some embodiments, the selective RBP4 antagonist is
  • the selective RBP4 antagonist is the compound having the structure:
  • R 3 R 4 R 2 1 wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl;
  • X is N or CR 6 , wherein R 6 is H, OH, or halogen; H A is absent or present, and when present, is ;
  • B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent;
  • X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl;
  • X 2 is C or N;
  • X 3 is CH or N;
  • R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylen
  • the selective RBP4 antagonist is the compound having the structure
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are ea c ndependently H, halogen, CF 3 , or C 1 -C 4 alkyl; and B has the structure: R 7 R 8 9 wherein ⁇ and ⁇ are each a bond that is present or absent;
  • X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl;
  • X 2 is C or N;
  • X 3 is CH or N;
  • R7, R8, and R9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O- alkyl, haloalkyl, cycloalkyl, O
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 Y B , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl; Y is alkyl; H A is absent or present, and when present, ; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O- alkyl,
  • the selective RBP4 antagonist is the compound having the structure R 3 R 3 R 4 R 2 R 3 R 4 R 2 R 4 R 2 1 Y .
  • the selective RBP4 antagonist is the compound wherein B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; and R7, R8, and R9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O(CO)- alkyl, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, NH-alkyl
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 11 N R N 12 13 wherein R 11 , R 12 , and R 13 are eac p y , halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O(CO)- alkyl, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)-NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R N 8 R 9 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R 8 R 9 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH2, C(O)-N(CH3)2, C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 7 R N 8 R 9 wherein R7, R8, and R9 are each indep , halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure: R 7 R 8 R 9 wherein R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)-N(CH 3 ) 2 , C(O)- NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 ; and R 10 is alkyl, alkenyl, or alkynyl.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 2 CH 3 , C(O)OH, or C(O)-NH 2.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and R 9 are each independently H, halogen, or alkyl. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 7 , R 8 , and R 9 are each H and the remaining one of R 7 , R 8 , and R 9 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 7 , R s , and R 9 is H and the remaining two of R 7 , R 8 , and Rgare each other than H.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein R 3 , R 8 , and Rg are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAC, CH 2 CH 2 C1, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein R 7 and R g are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAC, CH 2 CH 2 C1, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure In some embodiments, the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and Rg are each independently H, CH 8 , Br Cl, F,
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein R 7 and R 9 are each independently H, CH3, Br, Cl, F, CH2CH2OH, CH2CH2OCH3, CH 2 CH 2 OAc, CH2CH2CI, CH2CH2F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B has the structure
  • the selective RBP4 antagonist is the compound wherein R 7 , R 8 , and Rg are each independently H, CH3, Br Cl, F, CH2CH2OH, CH2CH2OCH3, CH 2 CH 2 OAc, CH2CH2CI, CH2CH2F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B2 has the structure
  • the selective RBP4 antagonist is the compound wherein Rg and Rg are each independently H, CH 3 , Br, Cl, F, CH2CH2OH, CH2CH2OCH3, CH 2 CH 2 OAc, CH2CH2CI, CH2CH2F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein:
  • R?, Rs, and Rg are each independently H, CH3, Br, Cl, F, CH2CH2OH,
  • the selective RBP4 antagonist is the compound wherein B or B2 has the structure
  • the selective RBP4 antagonist is the compound wherein:
  • R? and Rg are each independently H, CH3, Br, Cl, F, CH2CH2OH, CH2CH2OCH3, CH 2 CH 2 OAc, CH2CH2CI, CH2CH2F, or CH 2 CH 2 Br; and Riois alkyl.
  • the selective RBP4 antagonist is the compound wherein B or B2 has the structure R 11 N R N 12 13 wherein R 11 , R 12 , and R 13 endently H, halogen, alkyl, alkylenyl-OH, alkylenyl 2 , y yl-OAc, alkylenyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)-NH 2 , C(O)- N(CH 3 ) 2 , C(O)-NHCH 3 , NHC(O)-N(CH 3 ) 2 , CN, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 2 CH 3 , C(O)OH, or C(O)-NH 2 .
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, halogen, or alkyl. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 11 , R 12 , and R 13 are each H and the remaining one of R 11 , R 12 , and R 13 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 11 , R 12 , and R 13 is H and the remaining two of R 11 , R 12 , and R 13 are each other than H.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure
  • the selective RBP4 antagonist is the compound wherein R 11 , R 12 , and R 13 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein B or B 2 has the structure R 11 N N 1 3 .
  • the selective RBP4 antagonist is the compound wherein R 11 and R 13 are each independently H, CH 3 , Br, Cl, F, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OAc, CH 2 CH 2 Cl, CH 2 CH 2 F, or CH 2 CH 2 Br.
  • the selective RBP4 antagonist is the compound wherein X is N.
  • the selective RBP4 antagonist is the compound wherein X is CH.
  • the selective RBP4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each H, t-Bu, Cl, F, or CF 3 .
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 or t-Bu. In some embodiments, the selective RBP4 antagonist is the compound wherein: R 1 , R 3 , and R 4 are each H; R 2 is halogen; and R 5 is CF 3 or t-Bu. In some embodiments, the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 or t-Bu.
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is CF 3 . In some embodiments, the selective RBP4 antagonist is the compound wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two or more of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H.
  • the selective RBP4 antagonist is the compound wherein three of R1, R2, R3, R4, and R5are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein three or more of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is
  • the selective RBP4 antagonist is the compound wherein B or B 2 is other than
  • the selective RBP4 antagonist is the compound having the structure: wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, alkyl, haloalkyl, O-haloalkyl, aryl, or heteroaryl; X is N or CR 6 , wherein R 6 is H, OH, or halogen; NH A is absent or present, and when present, ; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkyl
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 R 1 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is , NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkylenyl-O- alkyl, haloalkyl, cycloalkyl, cyclo
  • the selective RBP4 antagonist is the compound having the structure: R 3 R 4 R 2 Y B , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; Y is alkyl; O NH A is absent or present, and when present, ; and B has the structure: R 7 R 8 R 9 wherein ⁇ and ⁇ are each a bond that is present or absent; X 1 is N, NH, or NR 10 , wherein R 10 is alkyl, alkenyl, or alkynyl; X 2 is C or N; X 3 is CH or N; R 7 , R 8 , and R 9 are each independently H, halogen, alkyl, alkenyl, alkynyl, alkylenyl-OH, alkylenyl-NH 2 , alkylenyl-OAc, alkyl
  • the selective RBP4 antagonist is the compound wherein one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein two of R 1 , R 2 , R 3 , R 4 , and R 5 are other than H. In some embodiments, the selective RBP4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each H, methyl, ethyl, phenyl, t-Bu, i-Pr, OCF 3 , CF 3 , OCF 2 CF 3 , CF 2 CF 3 , Cl, Br, or F.
  • the selective RBP4 antagonist is the compound wherein: R 1 , R 2 , R 3 , and R 4 are each H; and R 5 is -H, OCF 3 , CF 2 CF 3 , methyl, ethyl, i-Pr, or phenyl. In some embodiments, the selective RPB4 antagonist is
  • the C20-D3-visual-chromophore-producing compound is in a form packaged in chylomicrons.
  • the present disclosure provides a method for treating a disease characterized by excessive or age-related lipofuscin accumulation in the retina in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the pharmaceutical composition of the present disclosure for a simultaneous, contemporaneous, or concomitant administration of the selective RBP4 antagonist and the C20-D3-visual- chromophore-producing compound.
  • the disease is further characterized by bisretinoid-mediated macular degeneration.
  • the amount of the selective RBP4 antagonist is effective to lower the serum concentration of RBP4 in the mammal, or the amount of the selective RBP4 antagonist is effective to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal.
  • the bisretinoid is A2E.
  • the bisretinoid is isoA2E.
  • the bisretinoid is A2-DHP-PE.
  • the bisretinoid is atRAL di-PE.
  • the disease characterized by age-related lipofuscin accumulation in the retina is Age-Related Macular
  • the disease characterized by age- related lipofuscin accumulation in the retina is dry (atrophic) Age-
  • the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease. In some embodiments of the method, the disease characterized by excessive lipofuscin accumulation in the retina is other forms of retinopathy caused by or associated with mutations in the ABCA4 gene, such as retinitis pigmentosa (RP19) or cone-rod dystrophy (CORD3).
  • RP19 retinitis pigmentosa
  • CORD3 cone-rod dystrophy
  • the disease characterized by excessive lipofuscin accumulation in the retina is Best disease.
  • the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy.
  • the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt-like macular dystrophy.
  • the administration is effective to reduce photoreceptor degeneration.
  • the bisretinoid-mediated macular degeneration is Age-Related Macular Degeneration or Stargardt Disease.
  • the bisretinoid-mediated macular degeneration is Age-Related Macular Degeneration.
  • the bisretinoid-mediated macular degeneration is dry (atrophic) Age-Related Macular Degeneration.
  • the bisretinoid-mediated macular degeneration is Stargardt Disease.
  • the bisretinoid-mediated macular degeneration is other forms of retinopathy caused by or associated with mutations in the ABCA4 gene, such as retinitis pigmentosa (RP19) or cone-rod dystrophy (CORD3).
  • the bisretinoid-mediated macular degeneration is Best disease.
  • the bisretinoid-mediated macular degeneration is Stargardt-like macular dystrophy.
  • the pharmaceutical composition of the present disclosure exhibits retinol-binding protein 4 (RBP4) antagonist activity as well as activity of promoting rhodopsin and cone opsins production.
  • RBP4 retinol-binding protein 4
  • the pharmaceutical composition of the present disclosure reduces circulating RBP4 levels and promotes rhodopsin and cone opsins production.
  • the pharmaceutical composition of the present disclosure may be used for the treatment of dry age-related macular degeneration (AMD).
  • AMD dry age-related macular degeneration
  • the pharmaceutical composition of the present disclosure may be used for the treatment of type 2 diabetes.
  • the pharmaceutical composition of the present disclosure may be used for the treatment of obesity.
  • the pharmaceutical composition of the present disclosure may be used for the treatment of insulin resistance.
  • the pharmaceutical composition of the present disclosure may be used for the treatment of cardiovascular disease.
  • the pharmaceutical composition of the present disclosure may be used for the treatment of hepatic steatosis. In some embodiments, the pharmaceutical composition of the present disclosure may be used for the treatment of non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides a method for treating a non-alcoholic fatty liver disease (NAFLD) in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the pharmaceutical composition of the present disclosure for a simultaneous, contemporaneous, or concomitant administration of the selective RBP4 antagonist and the C20-D3-visual-chromophore-producing compound.
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides a method for treating gout in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising administering to the mammal an effective amount of the pharmaceutical composition of the present disclosure for a simultaneous, contemporaneous, or concomitant administration of the selective RBP4 antagonist and the C20-D3-visual-chromophore-producing compound.
  • the mammal is afflicted with a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • the method further comprises a step of determining, or having determined, the level of RBP4 in adipose tissue in the mammal and administering to the mammal the pharmaceutical composition of the present disclosure if the level of RBP4 in adipose tissue is elevated.
  • the method further comprises a step of determining, or having determined, the level of RBP4 in serum in the mammal and administering to the mammal the pharmaceutical composition of the present disclosure if the level of RBP4 in serum is elevated.
  • the amount of the selective RBP4 antagonist is effective in reducing RBP4 levels in adipose tissue in the mammal.
  • the amount of the selective RBP4 antagonist is effective in reducing RBP4 levels in serum in the mammal.
  • the amount of the selective RBP4 antagonist is effective in reducing uric acid levels in the serum of the mammal.
  • the amount of the selective RBP4 antagonist is effective to normalize the concentration of triglycerides in the liver of the mammal.
  • the amount of the selective RBP4 antagonist is effective to normalize the concentration of free fatty acids in the serum of the mammal.
  • the amount of the selective RBP4 antagonist is effective to normalize the concentration of free fatty acids in the liver of the mammal.
  • the amount of the selective RBP4 antagonist is effective to prevent trafficking of a fatty acid by RBP4.
  • the amount of the selective RBP4 antagonist is effective to prevent trafficking of a fatty acid to the liver by RBP4.
  • the amount of the selective RBP4 antagonist is effective to inhibit binding between RBP4 and a fatty acid.
  • the fatty acid is from adipose tissue. In some embodiments of the method, the mammal does not have elevated serum RBP4 levels.
  • the mammal has elevated serum RBP4 levels.
  • the serum RBP4 level of the mammal is elevated by more than 3 micrograms per ml.
  • the NAFLD is a hepatic steatosis selected from simple hepatic steatosis and mild hepatic steatosis.
  • the amount of the selective RBP4 antagonist is 5-1000 mg, 5-800 mg, 5-200 mg, 45-200 mg, 45-1000 mg, 45-800 mg, 10-50 mg, 96 mg, 24 mg, or 10 mg per day.
  • the second agent is DPOFA. In some embodiments of the method, the mammal is afflicted with gout.
  • the amount of the second agent is effective in increasing uric acid clearance in the mammal.
  • the amount of the second agent is effective in increasing uric acid levels in the urine of the mammal.
  • the preventing comprises reducing uric acid levels in the blood of the mammal. In some embodiments of the method, the preventing comprises increasing uric acid clearance in the mammal.
  • the preventing comprises decreasing uric acid reabsorption in the kidneys of the mammal.
  • the preventing comprises increasing renal clearance of uric acid in the mammal.
  • the gout is chronic gout.
  • the gout is acute gout.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist prevents a recurrence of chronic gout.
  • the mammal is female and the administration of the selective RBP4 antagonist reduces the uric acid level to 2.4-6.0 mg/dL.
  • the mammal is male and the administration of the selective RBP4 antagonist reduces the uric acid level to 3.4-7.0 mg/dL.
  • the administration of the selective RBP4 antagonist reduces uric acid levels in the mammal to less than 7 mg/dL.
  • the pharmaceutical composition of the present disclosure and the second agent are administered sequentially, simultaneously, contemporaneously, or concomitantly, in which in a sequential administration, the pharmaceutical composition of the present disclosure may be administered first or the second agent may be administered first.
  • the present disclosure provides the pharmaceutical composition of the present disclosure for use in a combination therapy together with a pharmaceutical composition comprising the second agent, for the treatment of a non-alcoholic fatty liver disease (NAFLD) or gout.
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure provides the pharmaceutical composition of the present disclosure comprising an amount of the selective RBP4 antagonist for use in treating a mammal afflicted with a non-alcoholic fatty liver disease (NAFLD) or gout as an add-on therapy to or in combination with the second agent.
  • NAFLD non-alcoholic fatty liver disease
  • the administration is oral.
  • the mammal is a human.
  • the present disclosure provides a method for treating a disease characterized by excessive or age-related lipofuscin accumulation in the retina in a mammal afflicted therewith, and for promoting rhodopsin and cone opsins production, comprising the steps of sequentially, simultaneously, contemporaneously, or concomitantly administering to the mammal an amount of a selective RBP4 antagonist effective to treat a disease characterized by excessive or age-related lipofuscin accumulation in the retina and an amount of a C20-D3- visual-chromophore-producing compound effective to promote rhodopsin and cone opsins production, in which in a sequential administration, the selective RBP4 antagonist may be administered first or the C20- D3-visual-chromophore-producing compound may be administered first.
  • the disease is further characterized by bisretinoid-mediated macular degeneration.
  • the amount of the selective RBP4 antagonist is effective to lower the serum concentration of RBP4 in the mammal, or the amount of the selective RBP4 antagonist is effective to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal.
  • the bisretinoid is A2E.
  • the bisretinoid is isoA2E.
  • the bisretinoid is A2-DHP-PE.
  • the bisretinoid is atRAL di-PE.
  • the disease characterized by age-related lipofuscin accumulation in the retina is Age-Related Macular
  • the disease characterized by age- related lipofuscin accumulation in the retina is dry (atrophic) Age-
  • the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease.
  • the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt-like macular dystrophy.
  • the bisretinoid-mediated macular degeneration is Stargardt Disease.
  • the mammal is afflicted with a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • a NAFLD selected from the group consisting of hepatic steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.
  • the method further comprises a step of determining, or having determined, the level of RBP4 in adipose tissue in the mammal and administering to the mammal the selective RBP4 antagonist and the C20-D3-visual-chromophore-producing compound if the level of RBP4 in adipose tissue is elevated.
  • the amount of the selective RBP4 antagonist is effective to normalize the concentration of triglycerides in the liver of the mammal. In some embodiments of the method, the amount of the selective RBP4 antagonist is effective to normalize the concentration of free fatty acids in the serum of the mammal. In some embodiments of the method, the amount of the selective RBP4 antagonist is effective to normalize the concentration of free fatty acids in the liver of the mammal. In some embodiments of the method, the amount of the selective RBP4 antagonist is effective to prevent trafficking of a fatty acid by RBP4. In some embodiments of the method, the amount of the selective RBP4 antagonist is effective to prevent trafficking of a fatty acid to the liver by RBP4. In some embodiments of the method, the amount of the selective RBP4 antagonist is effective to inhibit binding between RBP4 and a fatty acid. In some embodiments of the method, the fatty acid is from adipose tissue.
  • the mammal does not have elevated serum RBP4 levels.
  • the mammal has elevated serum RBP4 levels.
  • the serum RBP4 level of the mammal is elevated by more than 3 micrograms per ml.
  • the amount of the selective RBP4 antagonist administered is 5-1000 mg, 5-800 mg, 5-200 mg, 45-200 mg, 45-1000 mg, 45-800 mg, 10-50 mg, 96 mg, 24 mg, or 10 mg per day.
  • the method further comprises administering an amount of a second agent which is (R)-(+)-(5,6- dichloro 2,3,9,9a-tetrahydro 3-oxo-9a-propyl-lH-fluoren-7- yl)oxy]acetic acid (DPOFA), a Nonsteroidal Anti-inflammatory Drug (NSAID) such as indomethacin, colchicine, lesinurad, corticosteroids (e.g., betamethasone, prednisone, dexamethasone, cortisone, hydrocortisone, methylprednisone, prednisolone), biologic anti-IL- lalpha/beta agents (e.g., canakinumab, rilonacept, anakinra), allopurinol, benzbromarone, pegloticase, and other forms of uricase enzymes, topiroxostat (FYX-051), ulodesine (SID-051),
  • the mammal is afflicted with gout.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist is effective in reducing uric acid levels in the blood of the mammal.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist is effective in decreasing uric acid reabsorption in the kidneys of the mammal.
  • the amount of the second agent is effective in increasing uric acid clearance in the mammal.
  • the amount of the second agent is effective in increasing uric acid levels in the urine of the mammal.
  • the amount of the second agent is effective in increasing renal clearance of uric acid in the mammal.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist is effective in reducing one or more symptoms associated with gout in the mammal.
  • the one or more symptoms associated with gout are selected from joint pain, joint inflammation, joint redness, and decreased range of motion at the joint.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist is effective in preventing gout in the mammal.
  • the preventing comprises increasing uric acid levels in the urine of the mammal. In some embodiments of the method, the preventing comprises reducing uric acid levels in the blood of the mammal.
  • the preventing comprises increasing uric acid clearance in the mammal.
  • the preventing comprises increasing renal clearance of uric acid in the mammal.
  • the preventing comprises reducing one or more symptoms associated with gout in the mammal.
  • the gout is chronic gout.
  • the gout is acute gout.
  • the amount of the second agent and/or the amount of the selective RBP4 antagonist prevents a recurrence of chronic gout.
  • the mammal is female and the administration of the selective RBP4 antagonist reduces the uric acid level to 2.4-6.0 mg/dL.
  • the mammal is male and the administration of the selective RBP4 antagonist reduces the uric acid level to 3.4-7.0 mg/dL. In some embodiments of the method, the administration of the selective RBP4 antagonist reduces uric acid levels in the mammal to less than 7 mg/dL.
  • the administration is oral.
  • the mammal is a human.
  • the C20-D3-visual-chromophore- producing compound is selected from the group consisting of C20-D3- retinol, C20-D3-retinaldehyde, C20-D3-retinyl esters, C20-D3-9-cis- retinol, C20-D3-9-cis-retinaldehye, C20-D3-9-cis-retinyl esters, C20- D3-ll-cis-retinol, C20-D3-ll-cis-retinaldehye, C20-D3-11-cis-retinyl esters, and C20-D3-C20'-D3-[3-carotene.
  • the C20-D3-visual-chromophore- producing compound is in a form packaged in chylomicrons.
  • the selective RBP4 antagonist is a compound having the structure: R 3 R 2 R 1 wherein L is a lin he structure H , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , C 1 -C 4 alkyl, aryl, or heteroaryl; R 6 is H, OH, or halogen, or is absent; sent or present, and when present, is a bond; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro-substituted indole; and the pyrazole, when substituted, is substituted with other than triflu
  • the selective RPB4 antagonist is the compound wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl. 4877-4589-0155v.1
  • the selective RPB4 antagonist is R 6 the compound wherein B.
  • the selective RBP4 antagonist is R 6 the compound wherein B'.
  • the selective RBP4 antagonist is the compound wherein R 6 2 , R 3 , R 4 , and R 5 are other than H, and R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H
  • the selective RBP4 antagonist is N the compound wherein 1 .
  • the selective RBP4 antagonist is the compound wherein , r present, and when present, is H, OH, or halogen, and when ⁇ is present, then R 6 is absent, and when ⁇ is absent, then R 6 is present.
  • the selective RBP4 antagonist is O the compound wherein 1 . In some embodiments o f the method, the selective RBP4 antagonist is X the compound wherein L is 2 . In some embodiments of the method, the selective RBP4 antagonist is the compound wherein R 6 , , . In some embodiments of the method, the selective RBP4 antagonist is O the compound wherein 2 . In some embodiments o t e met od, t e se ect ve antagonist is O , O , , , , , , , , , O , CF 3 , CH 3 F F H 3 , H 3 , H 3 , F 3
  • the selective RBP4 antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Figure 25 shows the dynamics of the scotopic ERG a-wave amplitude elicited at the 1.89 log cd*s/m2 light intensity in the three groups of mice.
  • ACPHS-14 given for 10 days to wild- type mice reduced the a-wave amplitude by 45% in comparison to untreated mice.
  • co-administration of ACPHS-14 with p-carotene induced an increase in a-wave amplitude back to the normal level seen in untreated mice. This data proves that p-carotene can be used as a highly effective "second component" of the present disclosure in implementing the co-drug strategy.
  • Partial reduction of rhodopsin associated with RBP4 lowering is at the core of mechanism-based ocular AEs (adverse effects) associated with pharmacological RBP4 reduction, and the experimental results show that co-administration with C20-D3-retinoid can partially restore the level of rhodopsin in ACPHS-52-treated mice.
  • Reduction of rhodopsin levels caused by pharmacological RBP4 reduction is at the core of mechanism-based ocular AEs such as nyctalopia, chromatopsia, and delayed dark adaptation.
  • the present disclosure shows that co-administration of C20-D3-retinyl ester with the compound that induces a pronounced serum RBP4 reduction can partially restore the level of rhodopsin.
  • the present disclosure constitutes proof of principle and the co- dosing data generated for the TTR ligand and a bispecific compound may be applied to any RBP4-lowering medication, including selective RBPE antagonists.
  • Cioffi C.L. et al. J. Med. Chem. 57, 7731-7757 (2014). Cioffi, C.L. et al. J. Med. Chem. 58, 5863-5888 (2015).

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Abstract

La présente invention concerne de nouvelles thérapies pour la dégénérescence maculaire, la stéatose hépatique non alcoolique (NAFLD) et l'arthrite goutteuse (goutte), basées sur un co-médicament qui représente un conjugué de deux entités chimiques distinctes, ainsi que sur la co-administration et l'administration successive des deux entités chimiques. Le premier composant (" antagoniste sélectif de la RBP4 ") est une entité chimique qui engage la RBP4 ( protéine 4 de liaison au rétinol) du complexe RBP4-TTR (transthyrétine), qui intervient dans l'administration du rétinol à la rétine. Ce composant réduit le trafic de rétinol de la circulation vers la rétine. Le deuxième composant (« composé produisant des chromophores visuels C20-D3 ») est un rétinoïde ou caroténoïde modifié en C20-D3 qui, après avoir été métabolisé par un mammifère, peut finalement produire un chromophore visuel C20-D3 qui représente le C20 --D3-9--cis--.retinaldehyde C20-D3-ll-cis-retinaldebyde dans la rétine. La deutération en position C20 réduit la formation du bisrétinoïde de la lipofuscine alors que d'autres fonctions (telles que la fourniture d'un précurseur pour la synthèse in vivo du chromophore visuel, le 11-cis-rétinaldéhyde) ne sont pas réduites.
PCT/US2024/034834 2023-06-20 2024-06-20 Nouveau co-médicament, co-administration et administration successive d'un antagoniste sélectif du rbp4 et du c20-d3-rétinol pour l'élimination des effets indésirables oculaires basés sur le mécanisme dans le traitement de la dégénérescence maculaire, de la stéatose hépatique non alcoolique (nafld) et de l'arthrite goutteuse (goutte) Pending WO2024263790A2 (fr)

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