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WO2004093860A1 - Inhibiteurs de proteinase de coronavirus apparente au virus du sras - Google Patents

Inhibiteurs de proteinase de coronavirus apparente au virus du sras Download PDF

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Publication number
WO2004093860A1
WO2004093860A1 PCT/IB2004/001307 IB2004001307W WO2004093860A1 WO 2004093860 A1 WO2004093860 A1 WO 2004093860A1 IB 2004001307 W IB2004001307 W IB 2004001307W WO 2004093860 A1 WO2004093860 A1 WO 2004093860A1
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group
alkyl
cycloalkyl
heterocycloalkyl
independently
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Shella Ann Fuhrman
David Allan Matthews
Amy Karen Patick
Paul Abraham Rejto
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to methods of inhibiting Severe Acute Respiratory Syndrome (SARS) viral replication activity comprising contacting a SARS-related coronavirus 3C-like proteinase with a therapeutically effective amount of a rhinovirus 3C protease inhibitor.
  • SARS Severe Acute Respiratory Syndrome
  • the invention further relates to pharmaceutical compositions containing the rhinovirus 3C proteinase (RVP) inhibitor in a mammal by administering effective amounts of such rhinovirus 3C proteinase inhibitor.
  • RVP rhinovirus 3C proteinase
  • SARS Severe Acute Respiratory Syndrome-related virus(es)
  • Coronavirus replication and transcription function is encoded by the so-called "replicase” gene (Thiel, Herold et al. 2001), which consists of two overlapping polyproteins that are extensively processed by viral proteases.
  • the C-proximal region is processed at eleven conserved interdomain junctions by the coronavirus main or "3C-like” protease (Ziebuhr, Snijder et al. 2000).
  • the name "3C- like” protease derives from certain similarities between the coronavirus enzyme and the well-known picornavirus 3C proteases (Gorbalenya, Koonin et al. 1989).
  • the picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others.
  • Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production.
  • the present invention provides methods of inhibiting the activity of a coronavirus 3C protease (also known as proteinase), comprising contacting the coronavirus 3C protease with an effective amount of a picornavirus inhibitor compound, and preferably a rhinovirus inhibitor compound or agent.
  • a coronavirus 3C protease also known as proteinase
  • the present invention provides a novel method of interfering with or preventing SARS viral replication activity comprising contacting a SARS protease with a therapeutically effective amount of a rhinovirus protease inhibitor.
  • the SARS coronavirus 3C-like protease inhibitor is administered orally or intravenously.
  • the present invention also provides a method of treating a condition that is mediated by coronavirus 3C-like protease activity in a patient by administering to said patient a pharmaceutically effective amount of a rhinovirus protease inhibitor.
  • the present invention also provides a method of targeting SARS inhibition as a means of treating indications caused by SARS-related viral infections.
  • the present invention also provides a method of targeting viral or cellular targets identified by using rhinovirus inhibitors against SARS coronavirus 3C-like protease for treating indications caused by SARS-related viral infections.
  • the present invention also provides a method of identifying cellular or viral pathways interfering with the functioning of the members of which could be used for treating indications caused by SARS infections by administering a rhinovirus protease inhibitor.
  • the present invention also provides a method of using rhinovirus protease inhibitors as tools for understanding mechanism of action of other SARS inhibitors.
  • the present invention also provides a method of using rhinovirus protease inhibitors for carrying out gene profiling experiments for monitoring the up or down regulation of genes for the purposed of identifying inhibitors for treating indications caused by SARS infections.
  • the present invention further provides a pharmaceutical composition for the treatment of SARS in a mammal containing an amount of a rhinovirus protease inhibitor that is effective in treating SARS and a pharmaceutically acceptable carrier.
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula I:
  • M is O or S;
  • R is H, F, an alkyl group, OH, SH, or an O-alkyl group;
  • R 2 and R5 are independently selected from H,
  • R' 12 is H, an alkyi group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR' ⁇ 3> -NR' ⁇ 3 R' ⁇ 4 , -C(0)-R' 13 , - S0 2 R' ⁇ 3 , or -C(S)R' ⁇ 3 , and R' 13 and R' M , independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
  • a 2 is C, CH, CF, S, P, Se, N, NR 15 , S(O), Se(O), P-OR 15 , or P-NR 15
  • R 7 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁇ 7 , -SR 17 , -NR 17 R 18 , -NR ⁇ 9 NR 17 R 18 , or -NR 17 OR 18 , wherein R 17 , RIB, and R 1 9 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group; or R 7 , together with R 3 or R 6 and the atoms to which they are attached, forms a heterocycloalkyl group; R 20 is H, OH, or any suitable organic moiety; and
  • Z and Zi are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(0)R 2 ⁇ , -C0 2 R 2 ⁇ , -CN, -C(0)NR 2 ⁇ ,R 2 2, -C(0)NR 21 OR 22 , -C(S)R 2 ⁇ , - C(S)NR 2 ⁇ R 2 2, -N0 2 , -SOR21, -SO2R21, -SO2NR21R22, -SO(NR 21 ⁇ R 22 ).
  • R 23 , and R 24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R 21 , R 22 . R 23 .
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula II:
  • Ri is:
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIA:
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIB:
  • R 10 is H or CH 3 ;
  • R 20 is H, OH, CH 2 OH, or OCH 2 Ph;
  • R 30 is H, OH, or OCH 2 Ph;
  • R 40 is H or CN;
  • R 50 is CH 2 CH 3 , CH 3 , CH 2 Ph, CH 2 CH 2 Ph, CH 2 CH 2 OH, or CH 2 (2-pyridyl); or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof.
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIC:
  • R 1 00 is CH 3 , phenyl, Ph(4-NCH 3 ), Ph(4-OCH 3 ), 2-pyridyl, or 2-furyl; or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof.
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula III:
  • R a is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, provided that R a1 is not a substituted pyrrolidinyl, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
  • R G is a substituent having the formula:
  • R f and R 9 are each independently H or lower alkyl; m is 0 or 1 ; p is an integer of from 0 to 5; Ai is CH or N; when p is 1, 2, 3, 4, or 5, A 2 is C(R tl )(R i ), N(R S ), S, S(O), S(0) 2 , or O, and when p is 0, A 2 is C(R h )(R i )(R i ), N(R i )(R i ), S(R i ), S(0)(R i ), S(0) 2 (R i ), or 0(R !
  • each R h , R 1 and R 1 is independently H or a lower alkyl group; each As present is independently C(R h )(R'), N(R j ), S, S(O), S(0) 2 , or O; where each R h , R 1 and R j is independently H or lower alkyl; when p is 1, 2, 3, 4, or 5, A 4 is N(R k ), C(R ll )(R i ), or O; and when p is 0, A 4 is N(R ls )(R'), C(R h )(R')(R i ), and O(R'), where each R h , R 1 and R 1 is independently H or lower alkyl, each R is H, alkyl, aryl, or acyl, and each R 1 is H, alkyl, or aryl; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by Ai, (A 2 ) m ,
  • R b is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIIA: wherein:
  • R a2 is an alkyl, aryl or heteroaryl group, where the alkyl, aryl or heteroar I group is unsubstituted or substituted with one or more suitable substituents; and R° is a substituent having the formula:
  • R f and R 9 are each independently H or lower alkyl; m is 0 or 1 ; p is an integer of from 0 to 5; A ⁇ s CH or N; when p is 1, 2, 3, 4, or 5, A 2 is C(R h )(R i ), N(R j ), S, S(O), S(0) 2 , or 0, and when p is 0, A 2 is C(R h )(R i )(R i ), N(R l )(R i ), S(R i ), S(0)(R i ), S(0) 2 (R i ), or O(R'), where each R h , R 1 and R' is independently H or a lower alkyl group; each A3 present is independently C(R h )(R').
  • R d is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • R b is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IIIB:
  • R a3 is an aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group is unsubstituted or substituted with one or more suitable substituents;
  • R° is a substituent having the formula:
  • R f and R g are each independently H or lower alkyl; m is 0 or 1 p is an inte iger of from O to 5;
  • Ai is CH oi • N; when p is 1, 2, 3, 4, or 5, A 2 is C(R h )(R'), N(R J ), S, S(O), S(0) 2 , or O, and when p is 0, A 2 is C(R h )(R i )(R i ), N(R i )(R i ), S(R'), S(0)(R ! ), S(0) 2 (R i ), or O(R), where each R , R !
  • each A 3 present is independently C(R h )(R i ), N(R'), S, S(0), S(0) 2 , or 0; where each R h , R' and R' is independently H or lower alkyl; when p is 1 , 2, 3, 4, or 5, A 4 is N(R k ), C(R h )(R'), or O; and when p is 0, A 4 is N(R k )(R'), C(R h )(R')(R i ), and O(R'), where each R h , R' and R 1 is independently H or lower alkyl, each R k is H, alkyl, aryl, or acyl, and each R 1 is H, alkyl, or aryl; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by Ai, (A 2 ) m , (A 3 ) p , A
  • R d is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • R b is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents
  • R e is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula NIC:
  • R a4 is an aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group, where the aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; and
  • R c is a substituent having the formula:
  • R f and R 9 are each independently H or lower alkyl; m is 0 or 1 ; p is an integer of from 0 to 5; Ai is CH or N; when p is 1 , 2, 3, 4, or 5, A is C(R h )(R'), N(R j ), S, S(O), S(0) 2 , or O, and when p is 0, A 2 is C(R h )(R i )(R i ), NfR'XR 1 ), S(R i ), S(0)(R !
  • each R h , R 1 and R j is independently H or a lower alkyl group; each A 3 present is independently C(R h )(R'), N(R J ), S, S(O), S(0) 2 , or O; where each R h , R 1 and R j is independently H or lower alkyl; when p is 1, 2, 3, 4, or 5, A 4 is N(R k ), C(R h )(R'), or O; and when p is 0, A, is N(R k )(R'), C(R h )(R i )(R i ), and O(R'), where each R h , R 1 and R ] is independently H or lower alkyl, each R k is H, alkyl, aryl, or acyl, and each R 1 is H, alkyl, or aryl; provided that no more than two heteroatoms occur consecutively in the above-de
  • R d is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • R b is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents
  • R e is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, -C(0)R n -C0 2 R ⁇ -CN, -C(O)NR n R 0 ,
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula IV:
  • Y is -N(Ry)-, -C(R y )(R y )-, or -O-, where each R y is independently H or lower alkyl;
  • Ri is H, F, an alkyl group, OH, SH, or an O-alkyl group;
  • R 2 and R 3 are each independently H H ; ; integer from 0 to 5, Ai is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 41 ), N(R 4 ⁇ ), S, S(O), S(0) 2 , and O, and A 4 is NH or NR ⁇ , where each R 41 is independently H or lower alkyl, provided that no more than 2 heteroatoms occur consecutively in the ring formed by Ai, A 2l
  • R 5 and R 6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
  • R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR17, -SR 17 , -NR 17 R ⁇ 8 , -NRigNR ⁇ R ⁇ , or -NR17OR18, where R 17 , i 8 , and Rig are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
  • R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N,
  • Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(0)R 2 ⁇ , -CO 2 R 21 , -CN, -C(0)NR 2 ⁇ R 22 , -C(0)NR 2 ⁇ OR 22 , - C(S)R 2 ⁇ , -C(S)NR 2 ⁇ R 22 , -N0 2 , -SOR 21l -S0 2 R 2 ⁇ , -S0 2 NR 21 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -SO3R2 1 , - PO(OR 2 ⁇ ) 2 , -PO(R 21 )(R 22 ), -PO(NR 21 R 22 )(OR 23 ), PO(NR2iR 22 )(NR2 3 R 2 4), -C(0)NR 21 NR 22 R23, or
  • R 2 ⁇ , R 22 , R 23 , and R 24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or any two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Zi are not both H; or Z ⁇ and Ri, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z ⁇ together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or a prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate thereof.
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of the formula V[S11]:
  • Y is -N(R y )-, -C(R y )(R y )-, or -0-, where each R y is independently H or lower alkyl; R 1 is selected from optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -
  • R 16 is selected from optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, and amine;
  • R 2 and R 8 are each independently selected from H, F, and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
  • R 3 and R 9 are each independently selected from H and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 , and -NR 17 OR 18 , where R 17 , R 18 , and R are each independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and acyl;
  • R 4 is a suitable organic moiety; each of R 5 , R 6 and R 7 is independently H, F, or lower alkyl; m is O or l; p is O, 1, 2, 3, 4, or 5;
  • Ai is CH or N; when m is 1, A 2 is selected from C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(0) 2 , and O; when p is not 0, each A 3 is independently selected from C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(0) 2 , and O; where R 10 , R 11 and R 12 are each independently H or lower alkyl; when p is not 0, A is selected from N(R 13 ), C(R 10 )(R 11 ), and O, and when p is 0, Aj is selected from
  • R 11 and R 12 are each independently H or lower alkyl, R 13 is H, alkyl, aryl, or acyl, and R 14 is H, alkyl, or aryl; provided that Ai, (A 2 ) m , (A 3 ),,, and A) together do not include more than two consecutive heteroatoms; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula VI:
  • R a is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl, arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof may be unsubstituted or substituted with one or more suitable substituents;
  • R is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents
  • R d is H, halo, hydroxyl, or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
  • R c is a moiety having the formula:
  • R s and R f are each independently H or a lower alkyl group; m is 0 or 1 , provided that when m is 1 , R a is not an amino-substituted alkylcarbonylalkyl or amino-substituted alkylcarbonylaminoalkyl group, and when m is 0, R a is selected from an alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl group, provided that R a is not substituted indolecarbonylaminoalkyl; p is an integer of from 0 to 5; Ai is CH or N; when p is 1, 2, 3, 4, or 5, A 2 is C(R 9 )(R h ), N(R , S, S(O), S(0) 2
  • each A 3 present is independently C(R 9 )(R h ), N(R'), S, S(O), S(0) 2 , or O, where each R 9 , R h and R 1 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A, is N(R j ), C(R 9 )(R h ), or O, and when p is 0, A, is N(R')(R k ),
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula VII:
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor of formula VI I A:
  • R a is substituted or unsubstituted heterocycloalkyl or heterocycloalkylalkyl; R is a substituent having the formula:
  • R f and R° are independently I- 1 or lower alkyl; m is 1; p is an integer • of from 1 to 5; Ai is CH or N;
  • a 2 is C(R h )(R i ), N(R'), S, S(O), S(0) 2 , or 0; where each R h , R 1 and R j is independently H or lower alkyl; each A 3 present is independently C(R h )(R i ), N(R S ), S, S(O), S(0) 2 , or O; where each R h , R 1 and R* is independently H or lower alkyl;
  • R° is H, halogen or a substituted or unsubstituted lower alkyl group
  • R d is H, halogen, hydroxyl, a substituted or unsubstituted alkyl, alkoxy or alkylthio group
  • R e is H or a substituted or unsubstituted alkylgroup
  • Z and Z 1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, -C(0)R ⁇ , -C0 2 R n , -CN, -C(0)NR"R°, -C(0)NR n OR°, -C(S)R n , -C(S)OR n , -C(S)NR n R°, -N0 2 , -SOR°, -S0 2 R ⁇ , -S0 2 NR ⁇ R°, -S0 2 (NR ⁇ )(OR°), -SONR ⁇ , -S0 3 R n , -PO(OR ⁇ ) 2 , -PO(OR ⁇ )(OR°), -PO(NR ⁇ R°)(OR p ), -PO(NR ⁇ R°)(NR p R q
  • the invention provides a method of interfering with or preventing SARS related coronavirus viral replication activity comprising contacting a SARS related coronavirus protease with a therapeutically effective amount of a rhinovirus 3C protease inhibitor selected from the group consisting of: thereof.
  • the method described above utilizes the rhinovirus inhibitor selected from the group consisting of: 2-(2-Phenylethyl)benzoic acid N-hydroxyamide;
  • 2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; trans-2-(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3-(R)-(1-hydroxymethyl-2-(S)-(1H-imidazol-4- yl)-ethylcarbamoyl)- hexanehydroxamic acid;
  • 6-Biphenyl-4-yI-3 (R)-2 (S)-hydroxy-(l (S)-hydroxymethyl-2,2-dimethyl- ⁇ ropylcarbamoyl)- hexanoic hydroxamic acid; 6-Biphenyl-4-yl-3-(2-hydroxy-1 hydroxmethyl-propylcarbamoyl)- hexanoic hydroxamic acid; trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid hydroxyamide; 1-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;
  • Fig. 1 is a sequence alignment of 3C-like protein translated from SARS genome (AY274119) with TGEV 3C-like proteinase (1 LVO) used for homology modeling. The location of the first indel was adjusted from the BLAST alignment to better reflect the multiple alignment of other coronavirus 3C- like proteins (Anand, Palm et al. 2002). 43% of the residues are identical in this alignment.
  • Fig. 2 depicts the twelve residues used to superimpose the 3C-like protein structures were identified by visual inspection. They include a region near the catalytic cysteine, the catalytic histidine, and a region of structurally conserved beta-strand.
  • Fig. 3 is a homology model for SARS 3C-like protease (atom-color wire) superimposed on the cocrystal structure of rhinovirus 3C protease (purple wire) bound to AG7088 (atom-color stick).
  • Fig.4 shows the hydrogen bond between AG7088 and rhinovirus 3C protease from the cocrystal structure (1CQQ), the corresponding hydrogen bonds between AG7088 and the model of SARS 3C protease when superimposed on the structure of rhinovirus 3C protease.
  • Four of the hydrogen bonds predicted between AG7088 and the SARS 3C protease model are also found in the cocrystal structure of TGEV (1LVO), where water or the small molecule 2-methyl-2,4-pentanediol replace the inhibitor.
  • Fig. 5 shows solvent accessible (Connolly) surface of the binding site of AG7088 in the crystal structure of rhinovirus 3C protease (upper panel) and the corresponding surface in the SARS 3C protease model (lower panel).
  • Fig. 6 shows the percent (%) identity between coronavirus 3C proteases including SARS (AY274119), MHV: murine hepatitis virus (M55148), BCoV: bovine coronavirus (Q8V440), PEDV: porcine epidemic diarrhea virus (Q91AV2), FIPV: feline infectious peritonitis virus (Q98VG9), TGEV: transmissible gastroenteritis virus (Q9IW05), HCoV: human coronavirus 229E (Q9DLN0), AIBV: avian infectious bronchitis virus (M95169).
  • Fig.7 is a phylogenetic tree describing the coronavirus 3C proteases.
  • Fig. 8 is a molecular model of compound 1 in the binding site of SARS 3C like protease.
  • Fig. 9 is a molecular model of compound 2 in the binding site of SARS 3C like protease.
  • Fig. 10 is a molecular model of compound 3 in the binding site of SARS 3C like protease.
  • Fig. 11 is a molecular model of compound 4 in the binding site of SARS 3C like protease.
  • Fig. 12 is a molecular model of compound 5 in the binding site of SARS 3C like protease.
  • Fig. 13 is a molecular model of compound 6 in the binding site of SARS 3C like protease.
  • Fig. 14 is a molecular model of compound 7 in the binding site of SARS 3C like protease.
  • Fig. 15 is a molecular model of compound 8 in the binding site of SARS 3C like protease
  • Fig. 16 is a molecular model of compound 9 in the binding site of SARS 3C like protease.
  • Fig. 17 is a molecular mode of compound 10 n the binding ite of SARS 3C like protease.
  • Fig. 18 is a molecular model of compound 11 n the binding ite of SARS 3C like protease.
  • Fig. 19 is a molecular model of compound 12 n the binding ite of SARS 3C like protease.
  • Fig. 20 is a molecular mode 1 of compound 13 n the binding ite of SARS 3C like protease.
  • Fig. 21 is a molecular model of compound 14 n the binding ite of SARS 3C like protease.
  • Fig. 22 is a molecular model of compound 15 n the binding ite of SARS 3C like protease.
  • Fig. 23 is a molecular model of compound 16 n the binding ite of SARS 3C like protease.
  • Fig. 24 is a molecular model of compound 17 n the binding te of SARS 3C like protease.
  • Fig. 25 is a molecular model of compound 18 n the binding ite of SARS 3C like protease.
  • Fig. 21 is a molecular model of compound 14 n the binding ite of SARS 3C like protease.
  • Fig. 22 is a molecular model of compound 15 n the binding ite of
  • Fig. 26 is a molecular mode of compound 19 n the binding ite of SARS 3C like protease.
  • Fig. 27 is a molecular mode of compound 20 n the binding ite of SARS 3C like protease.
  • Fig. 28 is a molecular mode of compound 21 n the binding ite of SARS 3C like protease.
  • Fig. 29 is a molecular model of compound 22 n the binding ite of SARS 3C like protease.
  • Fig. 30 is a molecular model of compound 23 n the binding ite of SARS 3C like protease.
  • Fig. 31 is a molecular model of compound 24 n the binding ite of SARS 3C like protease.
  • Fig. 32 is a molecular model of compound 25 n the binding ite of SARS 3C like protease.
  • Fig. 33 is a molecular model of compound 26 n the binding ite of SARS
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties (including fused and bridged bicyclic and spirocyclic moieties), or a combination of the foregoing moieties.
  • cyclic moieties including fused and bridged bicyclic and spirocyclic moieties, or a combination of the foregoing moieties.
  • the group must have at least three carbon atoms.
  • a “lower alkyl” is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
  • heteroalkyl refers to a straight- or branched-chain alkyl group having from 2 to 12 atoms in the chain, one or more of which is a heteroatom selected from S, O, and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary amines, alkyl sulfides and the like.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • carbocycle refers to a saturated, partially saturated, unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic, ring structure having only carbon ring atoms (no heteroatoms, i.e., non-carbon ring atoms).
  • exemplary carbocycles include cycloalkyl, aryl, and cycloalkyl-aryl groups.
  • heterocycle refers to a saturated, partially saturated, unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic, ring structure having one or more heteroatoms selected from N, O, and S.
  • exemplary heterocycles include heterocycloalkyl, heteroaryl, and heterocycloalkyl- heteroaryl groups.
  • a "cycloalkyl group” is intended to mean a saturated or partially saturated, monocyclic, or fused or spiro polycyclic, ring structure having a total of from 3 to 18 carbon ring atoms (but no heteroatoms).
  • Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and like groups.
  • heterocycloalkyl group is intended to mean a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated, and has a total of from 3 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, and like groups.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • 4-10 membered heterocyclic includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl.
  • Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indoliny
  • aromatic heterocyclic groups are pyridinyl, imidazolyl pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl quinoxalinyl,
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • heteroaryl group is intended to mean a monocyclic or fused or spiro polycyclic, aromatic ring structure having from 4 to 18 ring atoms, including from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyrrolyl, thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl, pyrazinyl, triazolyl, tetrazolyl, indolyl, quinolinyl, quinoxalinyl, benzthiazolyl, benzodioxinyl, benzodioxolyl, benzooxa ⁇ olyl, and the like.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • amino is intended to mean the -NH 2 radical.
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
  • a pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzo
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents.
  • SARS-inhibiting agent means any rhinovirus protease inhibitor compound represented by formula I or a pharmaceutically acceptable salt, hydrate, prodrug, active metabolite or solvate thereof.
  • examples of rhinovirus protease inhibitors can be found in, but not limited to, U.S. Application Serial Nos. 09/301977 and 09/726376, which are incorporated herein in their entirety by reference.
  • processes mediated by rhinovirus protease refers to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the rhinovirus inhibitors described herein (e.g., SARS- related virus). Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
  • SARS-related coronavirus SARS
  • the term "interfering with or preventing" SARS-related coronavirus ("SARS") viral replication in a cell means to reduce SARS replication or production of SARS components necessary for progeny virus in a cell as compared to a cell not being transiently or stably transduced with the ribozyme or a vector encoding the ribozyme.
  • Simple and convenient assays to determine if SARS viral replication has been reduced include an ELISA assay for the presence, absence, or reduced presence of anti-SARS antibodies in the blood of the subject (Nasoff et al., PNAS 88:5462-5466, 1991), RT-PCR (Yu et al., in Viral Hepatitis and Liver Disease 574-477, Nishioka, Suzuki and Mishiro (Eds.); Springer-Verlag Tokyo, 1994). Such methods are well known to those of ordinary skill in the art.
  • total RNA from transduced and infected "control" cells can be isolated and subjected to analysis by dot blot or northern blot and probed with SARS specific DNA to determine if SARS replication is reduced.
  • reduction of SARS protein expression can also be used as an indicator of inhibition of SARS replication. A greater than fifty percent reduction in SARS replication as compared to control cells typically quantitates a prevention of SARS replication.
  • pharmaceutically acceptable carrier refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a hydroxamate compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent.
  • active metabolite refers to a pharmacologically active product produced through metabolism in the body of a specified hydroxamate compound or salt thereof.
  • Prodrugs and active metabolites of the inhibitor compounds described herein may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40:2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7):765-767 (1997); Bagshawe, Drug Dev. Res., 34:220-230 (1995); Bodor, Advances in Drug Res., 13:224-331 (1984); Bundgaard, "Design of Prodrugs” (Elsevier Press, 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al.
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • an inhibitor compound used in the method of the invention is a base
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like), or with an organic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), and the like.
  • an inorganic acid such
  • an inhibitor compound used in the method of the invention is an acid
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base (such as an amine (primary, secondary, or tertiary)), an alkali metal hydroxide, or alkaline earth metal hydroxide.
  • suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary amines, secondary amines, tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia such as primary amines, secondary amines, tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine)
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • inhibitor compounds, prodrugs, salts, or solvates that are solids
  • the hydroxamate compound, prodrugs, salts, and solvates used in the method of the invention may exist in different polymorph or crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
  • the hydroxamate compound, salts, prodrugs and solvates used in the method of the invention may exist as tautomers, all of which are intended to be within the broad scope ofthe present invention.
  • the inhibitor compounds, salts, prodrugs and solvates used in the method of the invention may have chiral centers.
  • the hydroxamate compound, salts, prodrugs and solvates may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope ofthe present invention.
  • an optically pure compound is one that is enantiomerically pure.
  • the term "optically pure" is intended to mean a compound comprising at least a sufficient activity.
  • an optically pure amount of a single enantiomer to yield a compound having the desired pharmacological pure compound of the invention comprises at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • “treating” or “treatment” means at least the mitigation of a disease condition in a human, that is alleviated by the inhibition of the activity of one or more coronaviral 3C-like proteases, including, but not limited to the 3C-like protease of the causative agent for SARS.
  • representative disease conditions include fever, dry cough, dyspnea, headache, hypoxemia, lymphopenia, elevated aminotransferase levels as well as viral titer.
  • Methods of treatment for mitigation of a disease condition include the use of one or more of the compounds in the invention in any conventionally acceptable manner.
  • the compound or compounds of the present invention are administered to a mammal, such as a human, in need thereof.
  • the mammal in need thereof is infected with a coronavirus such as the causative agent of SARS.
  • the present invention also includes prophylactic methods, comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof to a mammal, such as a human, at risk for infection by a coronavirus.
  • a mammal such as a human
  • an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof is administered to a human at risk for infection by the causative agent for SARS.
  • the prophylactic methods of the invention include the use of one or more of the compounds in the invention in any conventionally acceptable manner.
  • the activity of the inhibitor compounds as inhibitors of SARS-related viral activity may be measured by any of the suitable methods available in the art, including in vivo and in vitro assays.
  • the activity of the compounds of the present invention as inhibitors of coronavirus 3C-like protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. Examples of suitable assays for activity measurements include the antiviral cell culture assays described herein as well as the antiprotease assays described herein, such as the assays described in Examples 1 through 3.
  • Administration of the inhibitor compounds and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available to those skilled in the art.
  • suitable modes of administration include oral, nasal, pulmonary, parenteral, topical, transdermal, and rectal. Oral, intravenous, and nasal deliveries are preferred.
  • a SARS-inhibiting agent may be administered as a pharmaceutical composition in any suitable pharmaceutical form.
  • suitable pharmaceutical forms include solid, semisolid, liquid, or lyopholized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
  • the SARS-inhibiting agent may be prepared as a solution using any of a variety of methodologies.
  • the SARS-inhibiting agent can be dissolved with acid (e.g., 1 M HCI) and diluted with a sufficient volume of a solution of 5% dextrose in water (D5W) to yield the desired final concentration of SARS-inhibiting agent (e.g., about 15 mM).
  • a solution of D5W containing about 15 mM HCI can be used to provide a solution of the SARS-inhibiting agent at the appropriate concentration.
  • the SARS-inhibiting agent can be prepared as a suspension using, for example, a 1% solution of carboxymethylcellulose (CMC).
  • compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
  • Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions.
  • Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid.
  • Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water.
  • the carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension.
  • a dose of the pharmaceutical composition may contain at least a therapeutically effective amount of an SARS-inhibiting agent and preferably is made up of one or more pharmaceutical dosage units.
  • the selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of SARS-related coronavirus activity, by any known or suitable method of administering the dose, including topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; intravenously; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
  • the composition can be administered before, with, and/or after introduction of the cytotoxic drug.
  • the composition is preferably introduced before radiotherapy is commenced.
  • therapeutically effective amount and “effective amount” are intended to mean the amount of an inventive agent that, when administered to a mammal in need of treatment, is sufficient to effect treatment for injury or disease conditions alleviated by the inhibition of SARS viral replication such as for potentiation of anti-cancer therapies or inhibition of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases.
  • the amount of a given SARS-inihibiting agent used in the method of the invention that will be therapeutically effective will vary depending upon factors such as the particular SARS-inihibiting agent, the disease condition and the severity thereof, the identity and characteristics of the mammal in need thereof, which amount may be routinely determined by artisans.
  • a dose that may be employed is from about 0.001 to about 1000 mg/kg body weight, preferably from about 0.1 to about 100 mg/kg body weight, and even more preferably from about 1 to about 50 mg/kg body weight, with courses of treatment repeated at appropriate intervals.
  • Protein functions required for coronavirus replication and transcription are encoded by the so-called "replicase” gene. Two overlapping polyproteins are translated from this gene and extensively processed by viral proteases. The C-proximal region is processed at eleven conserved interdomain junctions by the coronavirus main or "3C-like” protease.
  • the name "3C-like” protease derives from certain similarities between the coronavirus enzyme and the well-known picomavirus 3C proteases. These include substrate preferences, use of cysteine as an active site nucleophile in catalysis, and similarities in their putative overall polypeptide folds.
  • Amino acids of the substrate in the protease cleavage site are numbered from the N to the C terminus as follows : -P3-P2-P1-P1 '-P2'-P3', with cleavage occurring between the P1 and P1' residues (Schechter & Berger, 1967). Substrate specificity is largely determined by the P2, P1 and P1' positions. Coronavirus main protease cleavage site specificities are highly conserved with a requirement for glutamine at P1 and a small amino acid at P1' (Journal of General Virology 83, pp. 595-599 (2002)).
  • Serine proteases such as factor Xa and thrombin, proteins involved in the blood-coagulation pathway with deep well defined S1 specificity pockets, have been targeted effectively with structurally diverse, small, noncovalent inhibitors and thus are exceptions to this generalization (19).
  • Peptidic substrates in which the scissile amide carbonyl is replaced by a Michael acceptor were first introduced as specific irreversible inhibitors of the cysteine protease papain by Hanzlik and coworkers (20, 21). We reasoned that, although this reaction is probably facilitated by the especially nucleophilic thiolateimidazolium ion pair in papain-like cysteine proteases, suitably activated Michael acceptors might also undergo addition by the presumably less nucleophilic catalytic cysteine of 3C and 3C-like proteases.
  • the inhibitor initially forms a reversible encounter complex with 3C, which can then undergo a chemical step (nucleophilic attack by the reactive site Cys) leading to stable covalent-bond formation.
  • the observed second-order rate constant for inactivation (k 0t ,s/l) depends on both the equilibrium binding constant k 2 /k ⁇ and the chemical rate for covalent bond formation k 3 (Meara, J. P. & Rich, D. H. (1995) Bioorg. Med. Chem. Lett. 5, 2277-2282).
  • Michael-acceptor inhibitors with specificity for 3C-like protease, as with 3C protease would likely achieve high rates of enzyme inactivation by combining good equilibrium binding with a modest rate of covalent-bond formation.
  • the rate of chemical inactivation presumably depends on not only the intrinsic electrophilic character of the inhibitor, but on how the reactive vinyl group is oriented relative to the Cys in the reactive site before nucleophilic attack and on the extent to which the transition state for the reaction can be stabilized by the enzyme.
  • Mechanism-based activation of an inherently weak Michael acceptor as a means of increasing the rate of the chemical step, and thus I I, is conceptually more attractive than attempting to achieve a similar effect by simply increasing intrinsic electrophilic reactivity, which would likely impart undesirable properties to such compounds.
  • the 50% cytotoxicity concentration (CC50) is calculated as the concentration of compound that decreases the percentage of neutral red produced in uninfected, compound-treated cells to 50% of that produced in uninfected, compound-free cells.
  • the therapeutic index is calculated by dividing the cytotoxicity (CC50) by the antiviral activity (EC50).
  • Example 2 - Viral yield assay The ability of compounds to protect cells by infection is evaluated in a virus yield assay similar to that described in A.K. Patick, S.L. Binford, M.A. Brothers, R.L. Jackson, C.E. Ford, M.D. Diem, F. Maldonado, P.S. Dragovich, R. Zhou, T.J. Prins, S.A. Fuhrman, J.W.
  • the cell monolayers are fixed with EAF (65% ethanol, 22% acetic acid, and 4% formaldehyde), stained with 1 % crystal violet and virus plaques enumerated. Data is expressed as plaque forming units (PFU) per ml.
  • the fifty percent EC50 is calculated as the concentration of compound that decreases the number of PFU/ml in infected, compound-treated cells to 50% of that produced by infected, compound-free cells.
  • Proteolytic activity of Coronavirus 3C protease is measured using a continuous fluorescence resonance energy transfer assay.
  • the substrate, DABCYL- GRAVFQGPVG- EDANS is prepared by modification ofthe core decapeptide (American Peptide Systems) and purified prior to use by HPLC using a C-18 resin (Alltech).
  • Other peptide cores are possible and may, for example, be derived from protease cleavage sites in the published sequence of the SARS coronavirus.
  • Preferred peptides retain the P1 and P1' amino acids (QG) of the above decapeptide (the proteolytic cleavage site).
  • QG P1' amino acids
  • other fluorescent probe/quencher combinations are possible.
  • the kobs is the first order rate constant for this reaction, and in the absence of any inhibitor represents the utilization of substrate.
  • the calculated kobs represents the rate of inactivation of coronavirus 3C protease.
  • the slope (kobs/ 1) of a plot of kobs vs. [I] is a measure of the avidity of the inhibitor for an enzyme. For very fast irreversible inhibitors, kobs/l is calculated from observations at only one or two [I] rather than as a slope.
  • a homology model for SARS 3C-like protease was created using the atomic coordinates for the recently published coronavirus "3C-like" protease as a template.
  • BLAST was employed to identify the 3C-like proteinase from the genomic RNA sequence of SARS (AY274119). Minor adjustment to the BLAST output resulted in an alignment with high percent identity and few gaps (Fig. 1), and this alignment was used to create a homology model with the MODELLER package in Insight2000 (Sanchez and Sali 2000).
  • Fig.2 Twelve residues with high structural conservation (Fig.2) were identified by visual inspection of the rhinovirus 3C (1CQQ) and TGEV 3C-like proteinase (1LVO) structures, as well as the SARS 3C-like proteinase homology model.
  • the structures were superimposed in a common reference frame by minimizing the root mean square difference (RMSD) between the backbone atoms of these residues, with RMSD ⁇ 0.6 Angstroms 2 . Inspection of the structures in the common reference frame demonstrates strong conservation of the side-chain conformations of the catalytic cysteine and histidine residues (Fig.3).
  • the S2 specificity pocket is more constrained in the coronavirus protease, suggesting that inhibitors having side chains smaller than fluorophenyalanine (as in AG7088) could be preferred.
  • This is consistent with the prevalence of Leu in many ofthe known coronavirus cleavage site sequences (Hegyi and Ziebuhr 2002).
  • Coronavirus main protease cleavage site specificities are highly conserved with a requirement for glutamine at P1 and a small amino acid at P1' (Hegyi and Ziebuhr 2002).
  • Picomavirus 3C proteases also favor cleavage sites with glutamine at P1 and either Gly or Ala at P1 '.
  • Michael acceptor based inhibitors with appropriate specificity elements should covalently inactivate coronavirus "3C-like" protease with both methyl and ethyl ester containing compounds.
  • Michael acceptor-based inhibitors having the criteria discussed above are assayed using the protease and antiviral assays described above in Examples 1-3.
  • the following compounds are identified as inhibitors of the 3C-like protease of the SARS-associated virus.
  • Table 1 below provides examples of inhibitor compounds that are useful as SARS-related 3C protease inhibitors. However, the invention is not limited to these particular examples. Table 1

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte à des procédés d'inhibition de l'activité de réplication virale d'un coronavirus apparenté au virus du SRAS, consistant à mettre une protéase de coronavirus apparenté au virus du SRAS en contact avec une quantité thérapeutique efficace d'un inhibiteur de protéase de rhinovirus, ainsi qu'à des compositions associées.
PCT/IB2004/001307 2003-04-21 2004-04-13 Inhibiteurs de proteinase de coronavirus apparente au virus du sras Ceased WO2004093860A1 (fr)

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US46455603P 2003-04-21 2003-04-21
US60/464,556 2003-04-21
US46819703P 2003-05-05 2003-05-05
US60/468,197 2003-05-05
US46850403P 2003-05-06 2003-05-06
US60/468,504 2003-05-06
US46906503P 2003-05-07 2003-05-07
US60/469,065 2003-05-07

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EP1704142A4 (fr) * 2003-12-31 2008-08-20 Taigen Biotechnology Co Ltd Inhibiteurs de la protease
US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2021202735A1 (fr) * 2020-03-31 2021-10-07 Diffusion Pharmaceuticals Llc Utilisation de composés d'amélioration de la diffusion pour le traitement d'une maladie respiratoire induite par des virus et des bactéries
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
CN113773259A (zh) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 病毒主蛋白酶抑制剂及其制备方法和用途
WO2022040186A1 (fr) * 2020-08-18 2022-02-24 Anixa Biosciences, Inc. Inhibiteurs de cystéine protéase mpro
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
WO2022156692A1 (fr) * 2021-01-22 2022-07-28 中国人民解放军军事科学院军事医学研究院 Inhibiteur peptidique cyclique de protéase virale, son procédé de préparation et son application dans des médicaments antiviraux
JP2023522990A (ja) * 2020-04-23 2023-06-01 パーデュー・リサーチ・ファウンデーション Ｓａｒｓの治療のための化合物
US12077605B2 (en) 2022-01-21 2024-09-03 Anixa Biosciences, Inc. Cysteine protease inhibitors and methods of use thereof
EP4263502B1 (fr) * 2020-12-18 2024-12-25 Nxera Pharma UK Limited Composés inhibiteurs de mpro du sars-cov-2

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1704142A4 (fr) * 2003-12-31 2008-08-20 Taigen Biotechnology Co Ltd Inhibiteurs de la protease
WO2021202735A1 (fr) * 2020-03-31 2021-10-07 Diffusion Pharmaceuticals Llc Utilisation de composés d'amélioration de la diffusion pour le traitement d'une maladie respiratoire induite par des virus et des bactéries
US11312704B2 (en) 2020-04-17 2022-04-26 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11472793B2 (en) 2020-04-17 2022-10-18 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
JP2023522990A (ja) * 2020-04-23 2023-06-01 パーデュー・リサーチ・ファウンデーション Ｓａｒｓの治療のための化合物
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11524940B1 (en) 2020-06-09 2022-12-13 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US12145911B2 (en) 2020-06-09 2024-11-19 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2022040186A1 (fr) * 2020-08-18 2022-02-24 Anixa Biosciences, Inc. Inhibiteurs de cystéine protéase mpro
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
EP4263502B1 (fr) * 2020-12-18 2024-12-25 Nxera Pharma UK Limited Composés inhibiteurs de mpro du sars-cov-2
WO2022156692A1 (fr) * 2021-01-22 2022-07-28 中国人民解放军军事科学院军事医学研究院 Inhibiteur peptidique cyclique de protéase virale, son procédé de préparation et son application dans des médicaments antiviraux
CN116648240A (zh) * 2021-01-22 2023-08-25 中国人民解放军军事科学院军事医学研究院 一种环肽类病毒蛋白酶抑制剂，其制备方法，及其在抗病毒药物中的应用
CN113773259A (zh) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 病毒主蛋白酶抑制剂及其制备方法和用途
US12077605B2 (en) 2022-01-21 2024-09-03 Anixa Biosciences, Inc. Cysteine protease inhibitors and methods of use thereof

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