WO2025136208A1

WO2025136208A1 - Senolytic compounds for use in the treatment and/or prevention of a headache disorder and/or chronic pain

Info

Publication number: WO2025136208A1
Application number: PCT/SE2024/051118
Authority: WO
Inventors: Saida HADJAB; Francois Lallemand
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-12-21
Filing date: 2024-12-19
Publication date: 2025-06-26
Anticipated expiration: 2026-06-21

Abstract

The present invention relates to a senolytic compound for use in the treatment of a headache disorder and/or chronic pain. The senolytic compound may be inhibitor or degrader of the Bcl-2 family proteins. For instance, the senolytic compound may be an anti-cancer drug such as Navitoclax or PROTAC Bcl-2 family proteins degraders.

Description

SENOLYTIC COMPOUNDS FOR USE IN THE TREATMENT AND/OR PREVENTION OF A HEADACHE DISORDER AND/OR CHRONIC PAIN

Technical field

The present invention relates to senolytic compounds. In particular, the present invention relates to a senolytic compound, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a headache disorder and/or chronic pain.

Background

Pain is a protective mechanism that is essential for preserving the functional integrity of the human body.

While pain often can be treated and relieved by simple medication there remains a large number of pain conditions that cause great suffering and are difficult to treat. It has been estimated that approximately 20 % of all adults worldwide suffer from pain such as chronic pain making it a global health crisis.

In medicine, the pain is usually classified as acute or chronic. The pain is denoted as being acute when it has a short duration and a recent onset whereas chronic pain is long-lasting such as lasting for a time period equal to or exceeding three months in humans.

There are many different kinds of pain medication and pain management strategies the use of which depends on the kind of pain, its cause and/or origin. A generality also is that these drugs must be used daily. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen can be purchased as over the counter (OTC) drugs to reduce pain, fever and inflammations. For more severe pain, opioid-based drugs are known as efficient pain killers. However, they require a prescription from a doctor and are associated with risks such as addiction, respiratory depression, constipation, nausea and vomiting. Moreover, in many cases, their efficiency decreases over time, and a substantial number of people do not respond to these drugs with pain relief.

The complexity of the pain conditions and the treatment options has prompted research and development into new types of pain medications. \N0 2020/081880 Al describes compositions targeting senescent cells and uses thereof. This document also describes a method for treating chemotherapy-induced peripheral neuropathy in a subject in need thereof wherein the method comprises administering a therapeutically effective amount of at least one senolytic agent which may be a means for inhibiting Bcl-xL or Bcl-2. Further, it is described that the senolytic agent may be ABT-263.

Thus, senolytic agents are described in the context of pathologic conditions involving pain.

More generally, senolytic drugs or compounds are a class of compounds allowing for the elimination of senescent cells, which are cells that may release substances such as inflammatory cytokines. These releases contribute to the Senescence-associated secretory Phenotype, SASP, a hallmark of senescent cells. It has been found that senescent cells accumulate with age and is a risk factor for many age-related diseases. Examples of senolytic drugs are anti-cancer drugs and antioxidants.

Still, there are many pain conditions for which there is no treatment or where the treatment options do not offer satisfactory pain relief. In particular, many headache disorders are difficult to treat and so is chronic pain. Therefore, there remains a need for efficient treatment of pain such as headache disorders and/or chronic pain.

Summary

It is an object of the present invention to overcome or at least mitigate problems associated with the treatment and/or prevention of a headache disorder and/or chronic pain. Further, it is an object of the present disclosure to provide aspects and/or advantages not provided by hitherto known techniques.

Accordingly, there is provided a senolytic compound, or a pharmaceutically acceptable salt solvate, stereoisomer, and/or ester thereof, for use in the treatment and/or prevention of a headache disorder and/or chronic pain.

There is also provided a use of a senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and/or ester thereof, for the manufacture of a medicament for the treatment and/or prevention of a headache disorder and/or chronic pain.

Further, there is provided a method for the treatment of a headache disorder and/or chronic pain, said method comprising administering to a patient an effective amount of a senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and/or ester thereof.

Brief description of the drawings

Figure 1A shows the detection of senescent pain-sensing neurons (nociceptors, DRG Noci) in mice DRG in pain condition (Injured) compared to control (Uninjured).

Figure IB shows the quantification of the in vivo detection of senescent cells in DRG sections of injured mice.

Figure 10 shows the detection of senescent DRG cells in human in pain condition (pain) compared to control condition (no pain).

Figure ID shows the detection of senescent pain-sensing neurons in human DRG (hDRG Noci) in pain condition (pain) compared to control condition (no pain).

Figure IE shows detection of senescence in rat trigeminal ganglia in a model of trigeminal neuralgia (TN) compared to control (sham).

Figure IF and 1G shows the detection of Senescence-Associated secretory Phenotype (SASP) in the cerebrospinal fluid of patient diagnosed with Cluster Headache.

Figure 2A shows the chemical structure of Navitoclax corresponding to CAS No. CAS. 923564-51-6.

Figure 2B shows the chemical structure of Dasatinib corresponding to CAS No 302962- 49-8

Figure 2C shows the chemical structure of Qurecetin corresponding to CAS No. 117- 39-5

Figure 2D shows the chemical structure of a PROTAC Bcl-xL degrader-2 corresponding to CAS No. 2920415-08-1.

Figure 2E shows the chemical structure of Venetoclax corresponding to CAS No. 1257044-40-8.

Figure 2F shows the chemical structure of PROTAC Bcl-2 degrader-1 corresponding to CAS No. 2378801-85-3.

Figure 3A shows a Von Frey test performed on uninjured hindlimb of animals treated with either vehicle or senolytic compound in Example 2 described herein.

Figure 3B shows a Von Frey test performed on injured hindlimb of animals treated with either vehicle or a senolytic compound in Example 2 described herein.

Figure 4 shows a Pinprick test performed on animals in Example 2 described herein.

Figure 5A shows the total distance in centimeters in the Open Field test as described in Example 3.

Figure 5B shows the zone duration (center or periphery) in the Open Field test as described in Example 3. Figure 6A shows the total distance in centimeters in the Elevated Plus Maze test as described in Example 3.

Figure 6B shows the zone duration (center, open arms, closed arms) in the Elevated Plus Maze test as described in Example 3.

Figure 7 shows the total time to cross the beam, and the neurological performance (neurological scoring) as described in Example 4.

Figure 8 shows the reduction in numbers of senescent pain-sensing neurons without treatment and after treatment with different senolytic compounds as described in Examples 2-5.

Description

The present disclosure provides a senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and/or ester thereof, for use in the treatment and/or prevention of pain, said pain being a headache disorder and/or chronic pain.

The present disclosure also provides a senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and/or ester thereof, for the manufacture of a medicament for use in the treatment and/or prevention of a headache disorder and/or chronic pain.

Further, there is provided a method for the treatment and/or prevention of a headache disorder and/or chronic pain, said method comprising administering to a patient such as a human an effective amount such as a therapeutically effective amount of a senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and/or ester thereof. As used herein, the expression "therapeutically effective amount" means an amount of the senolytic compound that is sufficient to induce the desired therapeutic effect.

Surprisingly, it has been found by the present inventors that senolytic compound(s) may be used for treating and/or preventing a headache disorder and/or chronic pain. While not being bound by any specific theory it is believed that headache disorders and chronic pain as described herein may be treated and/or prevented by subjecting painsensing neurons to senescence using the senolytic compounds described herein.

More specifically, the inventors have found that pain, such as pain related to a headache disorder and/or to chronic pain, may be prevented and/or treated by targeting senescent pain-sensing neurons using senolytic compounds as described herein. Administration of a senolytic compound to a subject experiencing pain may advantageously target senescent pain-sensing neurons, inducing selective apoptosis in these cells and thereby effectively removing said senescent pain-sensing neurons from the subject, thereby alleviating pain from said subject.

Further, it was found by the present inventors that senolytic compounds administered to rodents in an animal model of pain, animals which exhibit an increased number of senescent pain-sensing neurons, may be efficient in reducing the number of senescent pain-sensing neurons and/or their senescent activity. It was further found by the present inventors that administration of senolytic compounds as described herein, to said rodents suffering from pain, lead to pain alleviation in these animals.

As used herein, the expression "senolytic compound" is used interchangeably with "senolytic drug" or "senolytic agent".

As used herein, senolytic compounds or drugs intend a class of drugs that selectively reduce and/or clear senescent cells, such as senescent pain-sensing neurons or neurons characterized by a senescent phenotype. If not cleared from a subject, senescent cells may remain in the body and release substances such as inflammatory substances, thereby increasing the risk for disease and disorders, such as pain conditions.

As used herein, senescent cells refer to senescent pain-sensing neurons as characterised by altered functionality and associated with the release of different factors as part of the Senescence Associated Secretory Phenotype (SASP). These senescent pain-sensing neurons contribute to pathological conditions such as pain.

While senolytic compounds target and aim to eliminate senescent cells, their mechanism of action can vary. The senolytic drugs may inhibit or degrade the Bcl-2 family proteins, i.e. the B-cell lymphoma-2 protein. Preferably, the senolytic drugs may inhibit or degrade the Bcl-2 family proteins members that have an anti-apoptotic action, for example Bcl-2 and/or Bcl-xL and/or Bcl-w and/or Mcl-1. The BCL2 family is a diverse group of proteins that play a crucial role in regulating cell death through apoptosis. While some members of this family are proapoptotic, others have anti-apoptotic functions. As used herein, Bcl2 family protein members inhibitors and degraders refer to compounds that inhibit or degrade one or more of the anti-apoptotic members of the BCL2 family. It is believed that inhibition or degradation of the anti-apoptotic Bcl- 2 family proteins may lead to apoptosis.

Advantageously, the senolytic compounds described herein have been found to be free or substantially free from a negative impact on the Central Nervous System. For example, the senolytic compounds have been found not to induce anxiety. Further, the senolytic compounds have been found not to negatively impact balance or the brain motor function(s).

Thus, there is provided a senolytic compound, for use as an inhibitor of at least one member of the Bcl-2 family proteins. For example, the inhibitor of the Bcl-2 family proteins may be a Bcl-2, a Bcl-xL, a Bcl-w, and/or a Mcl-1 inhibitor, such as the anticancer drug Navitoclax (also denominated ABT-263).

Further, there is provided a senolytic compound for use as a degrader of at least one member of the Bcl-2 family proteins. For example, the Bcl-2 family protein degrader may be a Mcl-1, a Bcl-2, and/or a Bcl-xL degrader. In an example, the senolytic compound may be a PROTAC degrader of the Bcl-2 family of proteins, i.e. is a PROTAC Bcl-2 degrader. As used herein, PROTAC stands for Proteolysis Targeting Chimera. The PROTAC degrader may exert its action by inducing proteolysis of the Bcl-2 family protein member(s). The PROTAC Bcl-2 degrader may comprise or consist of a protein of interest ligand (abbreviated POI) connected to an E3 ligase ligand via a linker, wherein the E3 ligase ligand is capable of binding to an E3 ubiquitin ligase, and the POI is able to bind to the target protein meant for degradation. Examples of PROTAC Bcl-2 family proteins degraders include the compounds shown in Figures 2D and 2F herein.

Further, the present inventors have discovered that PROTACs, regardless of the E3 ligase ligand used, the linker size and length, or the specific BCL2 family member targeted (such as BCL-XL or BCL2, and MCL-1), when administered to rodents exhibiting an increased number of senescent pain-sensing neurons, all can be effective in reducing the senescent activity of these neurons and/or decreasing their number. Additionally, the present inventors found that administering senolytic compounds, as described herein, to mice suffering from pain may lead to pain alleviation.

An advantage of this therapeutic approach utilizing senolytic compounds, unlike the way opioids work, is that it preserves normal pain function in the treated subject while reducing the pathological pain associated with senescent cells. Unlike opioids, which can disrupt normal pain signalling and lead to dependence, senolytic drugs, especially PROTACs targeting BCL2 family members, target the root cause of pain by eliminating senescent cells, thus preserving normal pain function. This is crucial for maintaining the body's natural pain response mechanism.

Further, the present inventors have discovered that BCL2 family protein degraders in the form of PROTACs can effectively alleviate pain at concentrations significantly lower than those required for BCL2 inhibitors used (Example 2). Additionally, it was found that just two single doses of these PROTAC degraders were sufficient to achieve significant pain relief. The use of PROTACs as BCL2 family members degraders offers a promising approach for pain management by providing targeted, efficient, and potentially safer therapeutic options.

In one embodiment of the invention, there is provided a senolytic compound for treating pain, wherein said pain is a headache or a headache disorder.

In another embodiment of the invention, there is provided a senolytic compound selected from the group PROTAC Bcl-2 family protein degraders, Dasatinib, Navitoclax, and Venetoclax, for use in the treatment and/or prevention of trigeminal autonomic cephalalgias, such as cluster headache.

According to a particular embodiment, the invention provides a senolytic compound selected from the PROTAC Bcl-2 family protein degraders, i.e., a PROTAC degrader targeting Bcl-2 family proteins, for treating headache or a headache disorder.

In another particular embodiment, there is provided a senolytic compound selected from the PROTAC Bcl-2 family protein degraders, for treating at least one headache disorder selected from the group migraine, tension-type headache, trigeminal autonomic cephalalgias, other primary headache disorder, secondary headache, painful cranial neuropathies and/or other facial pains.

According to a further particular embodiment, there is provided a senolytic compound selected from the PROTAC Bcl-2 family protein degraders, for treating, trigeminal autonomic cephalalgias, such as cluster headache.

Further examples of PROTAC Bcl-2 degraders that may be used as senolytic compounds described herein include PROTAC Bcl-2 degraders including a CEREBLON ligand (abbreviated CRBN) such as Lenalidomide and pomalidomide and variants of those as E3 ligase ligand. It will be appreciated that pomalidomide has the CAS No. 19171-19-

18 and Lenalidomide has CAS No.191732-72-6.

Surprisingly, and advantageously, the CEREBLON ligand CRBN described herein has been found by the inventors to alleviate chronic pain in an animal chronic constriction injury model of chronic pain using only two doses.

Alternatively, the E3 ligase ligand may be a von Hippel-Lindau ligand such as in the compound shown in Figure ID herein.

In still a further example, the E3 ligase ligand may be a ligand for an E3 ligase which is provided by one or more of the following E3 ligase genes, which are expressed in both the trigeminal ganglia and in the dorsal root ganglia:

Hecwl

Rnfll

Rnfl87

Rnf7

Trim72

Trim2

Brap

Pja2

Anapcll

Aff4

Amfr

Prpfl9

Mkrnl

Trim36

Rnfl49

Rspryl

Rnfl22

Herd

Plagll

Hectd4

Maea

Rnf220

Rnf5

Rnfl57

Rnfl81

Xiap

Pelil

Rnfll5

Rnfl3

Rlim

Syvnl

Trim67

Pjal

Rnfl25

Dzip3

Triml3

Herc3

Wwpl Trim56 Vpsl8 Trim32 Lonrf2 Rnfl50 Trim9 Scafll Traf3 Lonrfl Trim25 Rnf215 Trim24 Rnfl52 Rnf8 Birc2 Znrf2 Bmil Dtx4 Shprh Midi Pcgf5 Trim27 Traf4 Rnf216 Rnf208 Rnfl30 Trim45 Rffl Rnf217 Pdzrn4 Vpsll Hecw2 Rad 18 Rnfl82 Rnfll2 Rnft2 Rnfl28 Lnxl Dtx2 Triml5 Hectd2 Herc6 Pcgf2 Rnf207 Trim7 Nhlrcl Mecom Pdzrn3 Rnfl65 Rnf32 Trim47 Trim59 Rnf26 Rnf219 Triml7 Mylip Trim68 Peli3 Plagl TrimlO Trim6 Rnf213 Rnfl80 Trim21 Brcal Birc3 Trim5 Dtxl Ragl Siah3 Neurl3 Rnfl7

Uhrfl Trim71 Rnf43 Dcstl Trim58 Rnf39

Further, there are senolytic compounds whose mode of action involves inhibition of tyrosine kinase(s), i.e. tyrosine kinase inhibitors. Thus, there is provided a senolytic compound which is a tyrosine kinase inhibitor such as an inhibitor of Abl and Src family tyrosine kinases. For example, the senolytic compound may be the tyrosine kinase inhibitor and anti-cancer drug Dasatinib.

Additionally or alternatively, the senolytic compound may be an antioxidant, i.e. a compound inhibiting oxidation which may take place by scavenging and/or neutralising free radicals. For instance, the senolytic compound may be a flavonoid such as Quercetin. Alternatively, the senolytic compound may be a compound which is not a flavonoid.

Thus, the senolytic compounds described herein may be one or more of the following: a Bcl-2 inhibitor, a Bcl-2 degrader, a Bcl-xL inhibitor, a Bcl-xL degrader, a Bcl-w inhibitor or degrader, a Mcl-1 inhibitor or degrader, a tyrosine kinase inhibitor, an antioxidant compound. For example, the senolytic compound(s) described herein may be a Bcl-2 inhibitor or tyrosine kinase inhibitor. In an example, senolytic compound(s) described herein may be a Bcl-2 degrader such as a PROTAC Bcl-2 degrader.

The senolytic compound may be a senolytic compound for use in the treatment and/or prevention of pain, wherein said pain is related to the presence of senescent painsensing neurons and/or the presence of senescent activity or a senescent phenotype in pain-sensing neurons. For example, the senolytic compound for use in the treatment and/or prevention of pain may be capable of reducing the number of senescent pain-sensing neurons and/or capable of reducing senescent activity of pain-sensing neurons in a subject in need thereof.

Advantageously, the senolytic compound of the present invention may selectively reduce or eliminate senescent pain-sensing neurons and/or neurons characterized by senescent activity or having a senescent phenotype in a subject suffering from pain related to senescent pain-sensing neurons.

In a further embodiment of the invention, there is provided a senolytic compound for preventing and/or treating pain, said senolytic compound specifically targeting senescent pain-sensing neurons and/or pain-sensing neurons having senescent activity and/or having a senescent phenotype.

According to a particular embodiment of the invention, there is provided a senolytic compound capable of reducing the number of senescent pain-sensing neurons and/or reducing the senescent activity and/or the senescent phenotype of pain-sensing neurons.

The senolytic compound may be a senolytic compound for use in the treatment and/or prevention of pain, wherein the pain comprises or consists of a headache disorder. For instance, the headache disorder described herein may be a headache disorder that is associated with trigeminal nerve compression such as autonomic cephalalgias. In a further example, the headache disorder may be associated with peripheral damage.

For example, the headache disorder may be one or more of the following: migraine, tension-type headache, trigeminal autonomic cephalalgias, other primary headache disorder, secondary headache, painful cranial neuropathies or other facial pains.

The trigeminal autonomic cephalalgias may be one or more of the following: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, hemicrania continua. In particular, the trigeminal autonomic cephalalgias may comprise or consist of cluster headache.

Further, there is provided a senolytic compound for use in the treatment of chronic pain. As used herein, chronic pain intends pain lasting for at least three months such as pain lasting for three months or more, six months or more or one year or more. The chronic pain may be continuous. Alternatively, the chronic pain may be "on" or "off".

For example, the chronic pain may be one or more of the following: chronic primary pain such as chronic widespread pain, chronic primary visceral pain, chronic primary musculoskeletal pain, chronic primary headache or orofacial pain, complex regional pain syndrome.

Additionally, or alternatively, the chronic pain may be one or more of the following: chronic cancer-related pain, chronic postsurgical or posttraumatic pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, chronic neuropathic pain, chronic secondary headache or orofacial pain. It will be appreciated that the chronic neuropathic pain may be one or more of the following: chronic peripheral neuropathic pain such as trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, painful radiculopathy.

The senolytic compound may be one or more senolytic compounds. Thus, the senolytic compound may be a single compound or a combination of two or more different senolytic compounds. For example, the senolytic compound may be one or more of the following: Navitoclax, Dasatinib, Quercetin. In particular, the senolytic compound may be Navitoclax and/or Dasatinib.

The senolytic compound may be administered to a patient or patient group in particular need thereof. For example, the senolytic compound may be administered to a patient suffering from a headache disorder or chronic pain. Additionally, or alternatively, the senolytic compound may be administered to a patient receiving end of life health care.

It will be appreciated that the senolytic compounds described herein may be provided in the form of a pharmaceutically acceptable salt such as an acid addition salt formed by combining the senolytic compound with an organic or inorganic acid in a desired ratio using methods known in the art.

The senolytic compound, or pharmaceutically acceptable salt thereof, may be provided in combination with a pharmaceutically acceptable excipient, adjuvant, diluent and/or absorption enhancer thereby forming a pharmaceutical composition. Thus, there is provided a pharmaceutical composition as described herein for use in the treatment and/or prevention of a headache disorder and/or chronic pain as described herein. Further, it will be appreciated that the senolytic compound may be administered orally, parenterally or locally on the nerve or affected ganglia. For example, the parental administration may be intravenous, intramuscular, subcutaneous or topical administration. Additionally, or alternatively, the administration may be craniofacial mucosal administration, such as intranasal administration, transnasal topical administration, transnasal injection, transoral administration, infrazygomatic administration, buccal administration, sublingual administration, conjunctival administration, rectal administration or intrathecal administration.

The administration may take place one or several times daily. Additionally, or alternatively, the senolytic compound may be administered in one or more treatment cycles. For example, the treatment may be applied in between bouts or in between recurrence.

The skilled person will understand that references to the "treatment of" a particular condition described herein (and similarly "treating") take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.

Further, the term prevention includes references to the prophylaxis and/or preventing of the disease, disorder and/or condition described herein. In particular, the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).

The invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

Examples Section

Abbreviations

Bcl-2 B-cell leukemia/lymphoma 2 protein

Bcl-xL B-cell lymphoma-extra large

CAS No. Chemical Abstract Service number

CCI Chronic constriction injury of peripheral nerve

CCL2 C-C Motif Chemokine Ligand 2 CCL3 C-C Motif Chemokine Ligand 3

CCL4 C-C Motif Chemokine Ligand 4

CCL13 C-C Motif Chemokine Ligand 13.

CFA Complete Freund's adjuvant

CSF1 Colony Stimulating Factor 1

CSF2 Colony Stimulating Factor 2

CXCL10 C-X-C Motif Chemokine Ligand 10

CXCL8 C-X-C Motif Chemokine Ligand 8

DMSO Dimethyl sulphoxide

DRG Dorsal Root Ganglia hDRG human Dorsal root ganglia hDRG Noci human dorsal root ganglia pain-sensing neurons DRG Noci Dorsal root ganglia pain-sensing neurons

EGF Epidermal Growth Factor g gram(s)

HGF Hepatocyte Growth Factor

IL6 Interleukin 6

IL7 Interleukin 7

IL18 Interleukin 18 kg kilogram(s)

Mcl-1 Myeloid cell Leukemia 1 mg milligram(s) min. minute(s) cm centimeter(s) mm millimeter(s)

MMP1 Matrix Metalloproteinase 1

MMP12 Matrix Metalloproteinase 12 ns not significant

OTF Open Field Test

SASP Senescence-Associated Secretory Phenotype

SEM standard error of the mean

TG trigeminal ganglia

TN trigeminal neuralgia

VEG FA Vascular Endothelial Growth Factor A General

Methods

Animals

Adult C57BL/6J mice.

Chronic constrictive injury mice model

The model used is the chronic constriction injury of peripheral nerve (CCI); the sciatic nerve has been widely described with minor differences in rodents as described in references 1-3. Briefly, mice were first anesthetized with isoflurane, and a small incision was made at the mid-thigh level on the right side. Ligatures were tied loosely around the sciatic nerve with approximately 0.5 mm spacing between ligatures. And then, the skin was closed by 5-0 silk suture.

Drug administration

The senolytic compounds were given orally. They were dissolved in DMSO to provide a stock solution which was stored at -80°C. The stock solution was diluted as 10% DMSO in corn oil prior to administration. Seven days post CCI injury, the senolytic compound or vehicle control (10% DMSO in corn oil) was administered by oral gavage once daily for either 10 consecutive days (Navitoclax or Venetoclax) or once weekly for 2 weeks (PROTAC Bcl-2 degrader and PROTAC Bcl-xL degrader).

Behavioral Tests

Von Frey test: Mechanical sensitivity was assessed by von Frey test in an up-down testing paradigm as previously described in References 4 and 5. Briefly, mice were placed in glass cylinders on a 6 x 6 mm wire mesh grid floor, acclimation lasted for 20 - 60 min. according to each mouse's need. The plantar surface of the hind paw was stimulated with a series of calibrated monofilaments (von Frey hairs; ranged between 0.008 and 2 g) and withdrawal or jerking of the paw is recorded as the pain threshold. Each filament was applied 6 times.

Pinprick assessment: Noxious mechanical sensitivity was assessed by pinprick test as previously described with minor modification as described in Reference 6. Briefly, mice were placed in Plexiglas chambers on top of a glass sheet. Acclimation lasted for 20 - 60 min. according to each mouse's need. A 25-gauge needle connected with a 1 g filament (von Frey hairs; Stoelting) was applied uniformly to the plantar surface of the hind paw without penetrating the skin. A score system was used according to the extent of the response. 0 = no response; 1 = move, look around to see what happened; 2 = brief quick lift or withdrawal or remove away of hind paw; 3 = brief quick shakes of hind paw, or jumps; 4 = high frequency of shaking, licking, flinching, or guarding. Mice were tested 4 times on each paw with a waiting time of 5 min.

Open Field Test: Animals were placed in a roofless 45x45cm square arena enclosed with 40cm walls and allowed to explore for 15 minutes while being recorded by a camera secured on the ceiling. Tracking and analysis was done using the EthoVision XT software where the arena was further partitioned into two zones: center (square area of 22.5x22.5cm in middle of the arena) and periphery (rest of arena close to walls). The total distance travelled, and the proportion of time spent in the two different zones with respect to the center-point of each animal were used as indicators of anxiety.

Elevated Plus Maze: Animals were placed in a plus (+) shaped arena elevated at 60cm from the ground and allowed to explore for 5 minutes while being recorded by a camera secured on the ceiling. Tracking and analysis was done using the EthoVision XT software where the arena was partitioned according to its design: two closed arms opposite to each other that are each 6x35cm enclosed by 15cm walls, two open arms opposite to each other with 6x35cm which are all connected to one another by a small 6x6cm center area. The total distance travelled and the proportion of time spent in the different types of zones with respect to the center-point of each animal were used as indicators of anxiety.

Beam Walk: Each animal and some bedding material was first placed for 2 minutes for habituation inside the goal box, which is 12x12x12cm elevated to 64cm from the ground and enclosed on all sides except for the entry side. Four beams with different diameters of 23mm, 20mm, 14mm and 11mm and length 105cm were used. Each test beam was placed straight with the end point in front of the goal box parallel to the ground with start and finish lines defined for a total length of 80cm in the middle of the beam. Animals were habituated on the largest beam until the ability to fully cross the beam without hesitation was demonstrated. A total of three trials were performed on each beam in order from largest to smallest, with at least 1 minute rest between trials in the goal box. Each trial was recorded on camera and the time required for the mouse to cross the beam from the start to finish and the usage of the injured leg were used as indicators of motor function.

In vivo and in silico analysis of senescence Senescence-Associated B-Galactosidase Staining: Mice were deeply euthanized by isoflurane and perfused with pre-cooled PBS. L4- L6 DRGs were quickly dissected, immediately frozen and then quickly imbedded in optimal cutting temperature embedding medium (OCT). SA-[3-galactosidase activity was detected by using a SA-[3- galactosidase staining kit (Cell Signaling Technology, #9860) at pH 6.0 according to the manufacturer's instructions with minor modification. Briefly, DRG sections were rinsed twice with PBS before fixation, followed by x-gal (pH 6.0) staining. After incubation (at 37°C) and upon signal appearance, staining solution was removed, rinsed three times by PBS, sealed and then immediately imaged.

SenMavo score: The SenMayo gene score was established by the MayoClinic to identify senescence based on the expression of more than hundred genes (a geneset defined by the MayoClinic as described in reference 9, reflecting senescence comprises of 119 and 125 genes for mouse and human respectively). It was calculated by the inventor lab on publicly available datasets and on the inventor lab own datasets, based on the gene expression count matrix by using score_genes function from Scanpy package.

Example 1

In this example, we examine samples for senescence markers in different pain conditions. The samples include human dorsal root ganglia, mice dorsal root ganglia, and rat trigeminal ganglia (TG). The samples also include human cerebrospinal fluid under both control and pain conditions. Senescence is identified using either the cellular Senescence Detection Kit for detecting senescence-associated betagalactosidase or the SenMayo score, which assesses senescence (or SASP profile) in silico using transcriptomic data.

Figure 1A boxplot representing the comparison of SenMayo score between uninjured and injured groups of the nociceptive cell lineage in mice DRG. The uninjured group consists of cells from the naive and sham conditions, while the cells of the injured groups are derived from axotomy, crush, nerve constriction and inflammatory (CFA) injury models combined. The score was calculated from the sc/snRNA-seq values. Please note that each of those pain models taken individually increased the SenMayo score.

Figure IB A bar plot representing the quantification of SA-[3-Galactosidase positive area in injured condition of cell from mice DRG with statistical level to denote the significant level of the positive area in each time point, DI, D7, D14 and D28, days after injury when compared to the day 0 (DO).

Figure 1C A boxplot representing the comparison of SenMayo score between groups of patients reporting with persistent pain (Pain) and without peristent pain (noPain), the dataset is described in reference 10. The score was calculated from bulk RNA-seq data.

Figure ID A boxplot representing the comparison of SenMayo score between nociceptive lineage cells (pain-sensing neurons) of patients reporting with and without pain. The score was calculated from the reconstructed scRNA-seq count matrix obtained from the deconvolution of the bulk RNA-seq data.

Figure IE A boxplot representing the comparison of SenMayo score between sham and trigeminal neuralgia (TN) groups from rat TG dataset. The dataset is described in reference 11. TN was done by the chronic compression of the trigeminal nerve root (CCT) operation.

For all the plots in Figure 1A-1E, the notations for the statistical significance are as followed ns P>0.05; * P<0.05; *** P<0.001; the tests were done with Mann-Whitney U.

These findings indicate that both humans experiencing pain and animal pain models experiencing pain exhibit an elevated presence of detectable senescence in painsensing neurons compared to control groups. These results show that trigeminal neuralgia is associated with senescence, chronic pain is associated with senescence, inflammatory pain is associated with senescence, neuropathic pain is associated with senescence.

Figure IF presents a Venn diagram illustrating the similarity between the gene set containing the Senescence-Associated Secretory Phenotype, SASP, genes that contribute to the SenMayo score and the genes corresponding to the proteins detected in the Olink cytokines panel, as referenced in Ran C et al. (2024). This diagram visually represents the overlap and unique genes within these two datasets, highlighting the relationship between senescence-associated secretory phenotype (SASP) genes and those identified through proteomic analysis.

The SenMayo gene list, which consists of 125 active molecules associated with the Senescence-Associated Secretory Phenotype, SASP, exhibits an interesting overlap with data from the Olink cytokines panel. This panel is a proteomic profiling platform used to measure protein expression levels in various biological samples. Specifically, 16 of these SASP molecules are shared between the two datasets and are the following CCL2, CCL3, CCL4, CSF1, CCL13, CSF2, CXCL10, CXCL8, EGF, HGF, IL6, IL7, MMP1, MMP12, VEGFA, IL18 and were quantified in patients with cluster headaches.

Figure 1G illustrates that in patients diagnosed with cluster headaches, whether they were in remission, or during an active bout, these 16 SASP molecules (identified above) were detected in the cerebrospinal fluid (CSF). Of these 16 molecules, 14 were found to be more abundant in the CSF of patients with Cluster Headache (either in remission (>3 weeks in remission) or during bouts (active), or both) compared to controls. This represents 87% of the detected SASP molecules being, on average, upregulated in the CSF of cluster headache patients (either in remission or during the active phase, or both) compared to the control group.

In the plotted 16 SASP molecules in Figure 1G, the central point represents the average value, while the extremities indicate the minimum and maximum values. The Y-axis displays the level of protein expression in NPX units on a Log2 scale. The X-axis categorizes the samples into three groups: control patients, patients diagnosed with cluster headaches in remission, and patients experiencing an active bout of cluster headaches. The dataset includes 20 control patients and 41 patients with cluster headaches, with 17 in remission and 24 during an active bout (according to the original study and here reanalyzed for the SASP molecules).

These findings suggest that cellular senescence is evident in cluster headache patients.

Example 2

In this example, the animals were adult C57BL/6J mice. The model being used was the Chronic constrictive injury mice model described above.

The pain sensitivity for mechanical pain or thermal pain as well as Pinprick scoring were evaluated before injury (baseline) and at different time points post injury. Therefore, each animal limb assessment has its own reference value as a control which is the baseline but can also be compared to the contralateral side which is not injured (un-injured). Moreover, a vehicle group (vol 10% DMSO in corn oil) is run in parallel for further assessment of the vehicle effect on pain sensitivity. The following senolytic compounds were tested : Navitoclax (ABT-263), Venetoclax (ABT-199; GDC-0199), PROTAC Bcl-2 degrader-1 as shown in Figure 2F, and PROTAC Bcl-xL degrader-2 as shown in Figure 2D. In this document, PROTAC Bcl-xL degrader as shown in Figure 2D may be denominated PROTAC Bcl-xL degrader-2: HY-139309, and PROTAC Bcl-2 degraderl, that degrade both Bcl-2 and Mcl-1, may be denominated PROTAC Bcl-2 degrader-1 : HY-125876.

Navitoclax

Navitoclax was purchased from MedChemExpress (HY-10087). Navitoclax was dissolved in DMSO to provide a stock solution which was stored at -80°C. Prior to administration, the stock solution was diluted with corn oil to provide a solution consisting of vol 10% stock solution and 90% corn oil. Seven days post CCI, Navitoclax in an amount of 100 mg/kg and vehicle control (i.e. 10% DMSO in corn oil), respectively, were administered by oral gavage once daily for 10 consecutive days.

Venetoclax

Venetoclax was purchased from MedChemExpress (HY-15531). Venetoclax was dissolved in DMSO to provide a stock solution which was stored at -80°C. Prior to administration, the stock solution was diluted with corn oil to provide a solution consisting of 10% stock solution and 90% corn oil. Seven days post CCI, Venotoclax in an amount of lOOmg/kg and vehicle control (i.e. 10% DMSO in corn oil), respectively, were administered by oral gavage once daily for 10 consecutive days.

PROTAC Bcl-2 deqrader-1 : HY-125876

PROTAC Bcl-2 degrader-1 was purchased from MedChemExpress (HY-125876). This compound has CAS No. 2378801-85-3. Further, this compound has the chemical structure shown in Figure 2F. The compound was dissolved in DMSO to provide a stock solution which was stored at -80°C. Prior to administration, the stock solution was diluted with corn oil to provide a solution consisting of 10% stock solution and 90% corn oil. Seven days post CCI, the PROTAC Bcl-2 degrader-1 HY-125876 was administered in an amount of 10 mg/kg, i.e. 10 milligrams per kilo bodyweight of the mouse, by oral gavage once weekly for 2 consecutive weeks.

PROTAC Bcl-xL degrader-2: HY-139309

PROTAC Bcl-xL degrader-2 was purchased from MedChemExpress (HY-139309). This compound has the chemical structure as shown in Figure 2D. The compound was dissolved in DMSO to provide a stock solution which was stored in -80°C. Prior to administration, the stock solution was diluted with corn oil to provide a solution consisting of 10% stock solution and 90% corn oil. Seven days post CCI, the PROTAC Bcl-xL degrader-2 HY-139309 was administered in an amount of 10 mg/kg by oral gavage once weekly for 2 consecutive weeks.

Behavioral tests were then performed as described above, and the results are shown in Figures 3A, 3B and 4.

Figures 3A and 3B shows the mechanical sensitivity as measured by von Frey tests, a method that evaluate mechanical allodynia and hyperalgesia for mice treated with vehicle (as described herein), Navitoclax, Venetoclax, PROTAC Bcl-2 deqrader-1: HY- 125876 and PROTAC Bcl-xL degrader-2: HY-139309. The drug administration started 7 days after CCI (CCI Day7). Pain behaviors assessments were performed at -2 days and -1 day before injury, which constitutes the baseline, as well as 7 days (CCI Day7), 16 days (CCI Day 16), 21 days (CCI Day 21), and 28 days (CCI Day 28) post injury. Von Frey tests were performed in the injured (right paw, Figure 3A) and uninjured (left paw, Figure 3B) hindlimbs and withdrawal thresholds were compared between drug, baseline and vehicle treated groups. Data are represented as the mean ± SEM (n = 6 animals for each drug treated groups and 12 animals for vehicle treated group). As shown in Figure 3A and 3B, the treatment with Navitoclax, PROTAC Bcl-2 degrader-1 : HY-125876 and PROTAC Bcl-xL degrader-2: HY-139309 eliminated or substantially eliminated mechanical allodynia and hyperalgesia at 4 weeks post injury as evidenced by the threshold withdrawal and value compared to the baseline and also compared to mice treated with the vehicle. Figures3A and 3B also shows that Venetoclax also improved mechanical sensitivity recovery albeit less than the other tested drugs. Figure 3B shows that the corresponding administration on the un-injured side had no or substantially no impact on the threshold withdrawal value.

Figure 4 shows the pain behaviour using a Pinprick test score for mice on the injured side, said mice being treated with vehicle (as described herein), Navitoclax, Venetoclax and PROTAC Bcl-xL degrader-1 :_HY-125876. Drug administration started 7 days after CCI. The Pinprick test was performed at -2 days and -1 day before injury, which constitutes the baseline, and 28 days post injury. Data are represented as the mean ± SEM (n=6 animals for each drug-treated groups and 6 animals for vehicle-treated group). Navitoclax at CCI 28 days was compared to vehicle at CCI 28 days post injury (n=6 in each group), other drug treatments were compared to the pinprick baseline (n=6 mice in each group). All mice treated with the drugs show no significant increase of pain behavior at 28days post injury, while injured mice treated with vehicle exhibit a large increase in pain response due to the injury. Thus, the mice treatedwith any of the drug compounds all had a lower pinprick score, often similar to baseline value or slightly lower showing, demonstrating that all drugs tested decreased pain in the chronic pain model, neuropathic pain. For navitoclax, mice had lower pinprick value than the vehicle, again showing that all drugs alleviate pain induced by the injury. Those results were consistent in both biological sex, male and female.

It was concluded that Bcl-2 family proteins inhibitors, such as Navitoclax or Venetoclax, and PROTAC Bcl-2 family proteins degraders, such as PROTAC Bcl-2 degrader-

125876 or PROTAC Bcl-xL degrader-2: HY-139309, can be used for treating chronic pain and/or headache as evidenced by the results provided in those experiments.

It is understood that this example, and the previous example, are relevant both for headache disorders and chronic pain as nerve compression model works for both dorsal root ganglia nerves and Trigeminal nerves. For Cluster headache there is evidence showing that the trigeminal nerve branch is compressed unilaterally by blood vessel as described in references 12-13, and therefore this example is relevant also for Cluster headache.

Thus, this example shows that a senolytic compounds, such as a Bcl-2 family proteins inhibitors and/or degraders, such as Navitoclax, Venetoclax and/or PROTAC Bcl-2 degrader, PROTAC Bcl-xL degrader, can be used in the treatment and/or prevention of chronic pain or pain disorders, or a headache or headache disorder such as Cluster headache.

Example 3

This experiment was performed to verify if the tested drug compounds have an impact on the Central Nervous System (CNS) by studying anxious behaviour of mice after administration of the tested drug compounds. The tests being used were the Open Field test (OFT) and the Elevated plus Maze test (EPM).

Samples of the drug compounds Venetoclax, PROTAC Bcl-2 degrader 1 :HY-125876 and PROTAC Bcl-xL degrader-2: HY-139309, and the vehicle being used as control, were prepared as described in Example 2. Mice were then subjected to testing in the Open Field test (OFT) and the Elevated plus Maze test (EPM). For each group treated with the drug compound and the control the number of animals was 6 (n=6 per group).

The results for the Open Field Test are shown in Figures 5A and 5B. The data are represented as the mean ± SEM. Figure 5A shows that the total distance in centimeters (cm) in the Open Field Test was the same for the control and the tested drug compounds. Figure 5B shows the zone duration in per cent (%) for the periphery duration and the center duration, respectively, and shows that they were the same for the control and the tested drug compounds groups.

The results for the Elevated Plus Maze test are shown in Figures 6A and 6B. The data are represented as the mean ± SEM. Figure 6A shows the total distance in centimeters (cm) in the Elevated Plus Maze test was the same for the control and the tested drug compounds. Figure 6B shows the zone duration in per cent (%) for the center duration, open arm duration and closed arm duration, and shows that they were the same for the control and the tested drug compounds groups.

Thus, no difference between the tested drug compounds was observed as evidenced by both the Open Field Test and the Elevated Plus Maze test. Further, a comparison of the tested drug compounds with the control revealed no difference showing that the tested drug compounds had no impact on the normal exploratory behaviour of the animals. It was concluded that that Bcl-2 family proteins inhibitor such as Venetoclax and Bcl-2 family proteins degrader such as PROTAC Bcl-2 degrader 1: HY-125876 and PROTAC Bcl-xL degrader-2: HY-139309 had no effect on basic higher brain function.

Example 4

This experiment was performed to verify if the tested drug compounds had an impact on motor function or balance. The test being used was the Beam Walking Test.

Samples of the drug compounds Venetoclax, PROTAC Bcl-2 degrader-1 : HY-125876 and PROTAC Bcl-xL degrader-2: HY-139309, and the vehicle being used as control, were prepared as described in Example 2 and then subjected to the Beam Walking Test. For each group treated with the drug compound and the control the number of animals was 6 (n=6 per group). The results are shown in Figure 7. Figure 7 shows the time in seconds (s) to cross the beam and shows no difference in time for the tested drug compounds and the control for crossing the small, medium, large and largest beams. Figure 7 lower panel shows the neurological assessment of the mice and shows that no difference in the assessment score was observed for the small, medium, large and largest beams.

Thus, no difference between the tested drug compounds was observed as evidenced by the Beam Walking Test. Further, a comparison of the tested drug compounds with the control revealed no difference showing that the tested drug compounds had no impact on motor function or balance as evidenced by the Beam Walking Test. It was concluded that that a Bcl-2 family protein inhibitor such as Venetoclax and a Bcl-2 family protein degrader such as PROTAC Bcl-2 degrader 1 :HY-125876 and PROTAC Bcl-xL degrader-2: HY-139309 had no effect on motor function or balance.

Example 5

Identification of senescent activity in peripherin-positive neurons (small diameter, pain-sensing neurons) was done by immunostaining. SA-p-galactosidase stained DRG sections from Example 1 were incubated with a primary antibody for peripherin (anti- peripherin (1:200; ab39374, Abeam) followed by incubation with a secondary fluorescently labeled antibody. The sections were then imaged using microscopy and the proportion of SA-p-galactosidase positive senescent cells in relation to peripherin positive small-diameter pain-sensing neurons was quantified. The results are shown in figure 8.

Figure 8 shows a bar plot representing the quantification of the proportion of SA-p- Galactosidase/peripherin double positive pain-sensing neurons to the total number of peripherin positive pain-sensing neurons in mouse dorsal root ganglia at day 28 after chronic constriction injury. The bar plot shows the proportion of SA-p-galactosidase and peripherin double positive cells in relation to all peripherin positive cells in injured animals without treatment, treated with vehicle (DMSO) or treated with senolytic compounds ABT263, Venetoclax, Protac Bcl2, or Protac Bcl-xl.

A selective removal of at least 70% of SA-p-galactosidase and peripherin double positive neurons among the small diameter peripherin-positive neurons was observed for all senolytic compounds tested. These findings indicate that senolytic compounds are capable of reducing the number of senescent pain-sensing neurons and/or that senolytic compounds are capable of reducing senescent activity or the senescent phenotype of pain-sensing neurons. These compounds can thus be used in the treatment and/or prevention of chronic pain or pain disorders, and/or to treat a headache or headache disorder such as Cluster headache. References

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2. Bennett, G. J. & Xie, Y.-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87-107 (1988).

3. Guan, Y. et al. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Proceedings of the National Academy of Sciences 107, 15933-15938 (2010).

4. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53, 55-63 (1994).

5. Bonin, R. P., Bories, C. & De Koninck, Y. A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments. Mol Pain 10, 26 (2014).

6. Rinwa, P. et al. Demise of nociceptive Schwann cells causes nerve retraction and pain hyperalgesia. Pain 162, 1816-1827 (2021).

7. Hu, S.-W. et al. Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain. J. Neurosci. 41, 9988-10003 (2021).

8. WO 2020/081880 Al

9. Saul, D. et al. A new gene set identifies senescent cells and predicts senescence- associated pathways across tissues. Nat Commun 13, 4827 (2022).

10. Ray, P. R. et al. RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain. Brain 146, 749-766 (2023).

11. Tao, R. et al. Using RNA-Seq to Explore the Hub Genes in the Trigeminal Root Entry Zone of Rats by Compression Injury. Pain Physician 24, E573-E581 (2021).

12. Salvesen, R. Cluster Headache. Current Treatment Options in Neurologyl:441- 449 (1999).

13. Mjaset, C and Russell, M. B. Secondary chronic cluster headache due to trigeminal nerve root compression. Acta Neurologica Scandinavica 6, 373-376 (2010). 14. Ran, C. et al. Elevated cytokin elevels in the central nervous system of cluster headache patients in bout and in remission. The Journal of Headache and Pain 25: 121 (2024)

Claims

1. A senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use in the treatment and/or prevention of pain, said pain being a headache disorder and/or chronic pain.

2. The senolytic compound for use according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, wherein the senolytic compound is an inhibitor or degrader of the Bcl-2 family proteins.

3. The senolytic compound for use according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, wherein the degrader of the Bcl-2 family proteins is a PROTAC Bcl-2 family proteins degrader, such as PROTAC Bcl-2 degrader, or a PROTAC Bcl-xL degrader.

4. The senolytic compound for use according to any of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, wherein said pain is related to senescent pain-sensing neurons and/or senescent activity in pain-sensing neurons.

5. The senolytic compound for use according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, wherein said pain is treated and/or prevented by reducing the number of senescent pain-sensing neurons and/or reducing the senescent activity of painsensing neurons.

6. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to any of the preceding claims, wherein the senolytic compound is not Fisetin.

7. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to any one of claims 1-6, wherein the pain is a headache disorder.

8. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to any one of claims 1-7, wherein the headache disorder is one or more of the following: migraine, tension-type headache, trigeminal autonomic cephalalgias, other primary headache disorder, secondary headache, painful cranial neuropathies or other facial pains.

9. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 8, wherein the headache disorder is trigeminal autonomic cephalalgias.

10. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 9, wherein the trigeminal autonomic cephalalgias are one or more of the following: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, hemicrania continua.

11. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 9 or 10, wherein the trigeminal autonomic cephalalgias is cluster headache.

12. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to any one of claims 1-6, wherein the pain is chronic pain.

13. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 12, wherein the chronic pain is one or more of the following: chronic primary pain such as chronic widespread pain, chronic primary visceral pain, chronic primary musculoskeletal pain, chronic primary headache or orofacial pain, complex regional pain syndrome.

14. The senolytic compound, or a pharmaceutically acceptable salt thereof, solvate, stereoisomer and/or ester for use according to claim 12, wherein the chronic pain is one or more of the following: chronic cancer-related pain, chronic postsurgical or posttraumatic pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, chronic neuropathic pain, chronic secondary headache or orofacial pain.

15. The senolytic compound, or a pharmaceutically acceptable salt thereof, solvate, stereoisomer and/or ester for use according to claim 14, wherein the chronic neuropathic pain is one or more of the following : chronic peripheral neuropathic pain such as trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, painful radiculopathy.

16. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to any one of claims 1-5 or 7-15, wherein the senolytic compound is one or more of the following:

17. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 16, wherein the senolytic compound is

18. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer and/or ester thereof, for use according to claim 16, wherein the senolytic compound is

19. The senolytic compound, or a pharmaceutically acceptable salt, solvate, stereoisomer or ester thereof, for use according to any one of the preceding claims, wherein the senolytic compound is administered to a patient diagnosed with a headache disorder or chronic pain, or a patient receiving end of life health care.