Ciluprevir: Difference between revisions

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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| IUPAC_name = (2''R'',6''S'',12''Z'',13a''S'',14a''R'',16a''S'')-6-[(Cyclopentyloxycarbonyl)amino]-2-({7-methoxy-2-[(propan-2-ylamino)-1,3-thiazol-4-yl]quinolin- 4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[''e'']pyrrolo[1,2-''a''][1,4]diazacyclopentadecine-14a(5''H'')-carboxylic acid
| IUPAC_name = (2''R'',6''S'',12''Z'',13a''S'',14a''R'',16a''S'')-6-[(Cyclopentyloxycarbonyl)amino]-2-({7-methoxy-2-[(propan-2-ylamino)-1,3-thiazol-4-yl]quinolin- 4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[''e'']pyrrolo[1,2-''a''] [1,4]diazacyclopentadecine-14a(5''H'')-carboxylic acid
| image = Ciluprevir.svg
| image = Ciluprevir.svg
| width = 285
| width = 285
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<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| protein_bound = >99.1%<ref name = "Tan">{{cite book|editor1-last=Tan|editor1-first=Seng-Lai|editor2-last=He|editor2-first=Yupeng|title=Hepatitis C: Antiviral Drug Discovery and Development|date=2011|publisher=Caister Academic Press|location=Norfolk, UK|isbn=978-1-904455-78-3|page=199}}</ref>
| protein_bound = >99.1%<ref name = "Tan">{{cite book|editor1-last=Tan|editor1-first=Seng-Lai|editor2-last=He|editor2-first=Yupeng | name-list-style = vanc |title=Hepatitis C: Antiviral Drug Discovery and Development|date=2011|publisher=Caister Academic Press|location=Norfolk, UK|isbn=978-1-904455-78-3|page=199}}</ref>
| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
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| ATCvet =
| ATCvet =
| ATC_prefix = None
| ATC_prefix = None
| ATC_suffix =
| ATC_suffix =
| DrugBank =
| DrugBank =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 75C8DU40T0
| UNII = 75C8DU40T0
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<!--Chemical data-->
<!--Chemical data-->
| C=40 | H=50 | N=6 | O=8 | S=1
| C=40 | H=50 | N=6 | O=8 | S=1
| smiles = O=C2N[C@]7(C(=O)O)C[C@H]7/C=C\CCCCC[C@H](NC(=O)OC1CCCC1)C(=O)N6[C@H]2C[C@@H](Oc3cc(nc4c3ccc(OC)c4)c5nc(sc5)NC(C)C)C6
| smiles = O=C2N[C@]7(C(=O)O)C[C@H]7/C=C\CCCCC[C@H](NC(=O)OC1CCCC1)C(=O)N6[C@H]2C[C@@H](Oc3cc(nc4c3ccc(OC)c4)c5nc(sc5)NC(C)C)C6
| StdInChI = 1S/C40H50N6O8S/c1-23(2)41-38-43-32(22-55-38)31-19-34(28-16-15-26(52-3)17-30(28)42-31)53-27-18-33-35(47)45-40(37(49)50)20-24(40)11-7-5-4-6-8-14-29(36(48)46(33)21-27)44-39(51)54-25-12-9-10-13-25/h7,11,15-17,19,22-25,27,29,33H,4-6,8-10,12-14,18,20-21H2,1-3H3,(H,41,43)(H,44,51)(H,45,47)(H,49,50)/b11-7-/t24-,27-,29+,33+,40-/m1/s1
| StdInChI = 1S/C40H50N6O8S/c1-23(2)41-38-43-32(22-55-38)31-19-34(28-16-15-26(52-3)17-30(28)42-31)53-27-18-33-35(47)45-40(37(49)50)20-24(40)11-7-5-4-6-8-14-29(36(48)46(33)21-27)44-39(51)54-25-12-9-10-13-25/h7,11,15-17,19,22-25,27,29,33H,4-6,8-10,12-14,18,20-21H2,1-3H3,(H,41,43)(H,44,51)(H,45,47)(H,49,50)/b11-7-/t24-,27-,29+,33+,40-/m1/s1
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}}
}}


'''Ciluprevir''' was a drug used experimentally in the treatment of [[hepatitis C]]. It is manufactured by [[Boehringer Ingelheim]] and developed under the research code of '''BILN 2061'''. It was the first-in-class [[NS3 (HCV)|NS3]]/[[NS4A|4A]] protease inhibitor to enter clinical development and tested in human.<ref>{{cite book | editor1-last = Tan | editor1-first = Seng-Lai | title = Hepatitis C Viruses: Genomes and Molecular Biology | date = 2006 | publisher = Horizon Bioscience | location = Norfolk (UK) | isbn = 978-1-904933-20-5 | url = https://www.ncbi.nlm.nih.gov/books/NBK1613/ | chapter = 6. HCV NS3-4A Serine Protease}}</ref> Ciluprevir is a potent competitive reversible inhibitor of NS3/4A protease from HCV genotype 1a (K<sub>i</sub> = 0.3 nM) and 1b (K<sub>i</sub> = 0.66 nM). It shows good selectivity for NS3 protease against representative serine and cysteine proteases, human leukocyte elastase and cathepsin B ([[IC50|IC<sub>50</sub>]] > 30 ''μ''M).<ref name = "Tan" />
'''Ciluprevir''' was a drug used experimentally in the treatment of [[hepatitis C]]. It is manufactured by [[Boehringer Ingelheim]] and developed under the research code of '''BILN 2061'''. It was the first-in-class [[NS3 (HCV)|NS3]]/[[NS4A|4A]] protease inhibitor to enter clinical development and tested in human.<ref>{{cite book | editor1-last = Tan | editor1-first = Seng-Lai | name-list-style = vanc | title = Hepatitis C Viruses: Genomes and Molecular Biology | date = 2006 | publisher = Horizon Bioscience | location = Norfolk (UK) | isbn = 978-1-904933-20-5 | url = https://www.ncbi.nlm.nih.gov/books/NBK1613/ | chapter = 6. HCV NS3-4A Serine Protease| pmid = 21250377 | last1 = Tan | first1 = S. L. }}</ref> Ciluprevir is a potent competitive reversible inhibitor of NS3/4A protease from HCV genotype 1a (K<sub>i</sub> = 0.3 nM) and 1b (K<sub>i</sub> = 0.66 nM). It shows good selectivity for NS3 protease against representative serine and cysteine proteases, human leukocyte elastase and cathepsin B ([[IC50|IC<sub>50</sub>]] > 30 ''μ''M).<ref name = "Tan" />


Its development was halted in phase Ib clinical trials because of toxicity in animals. However, ciluprevir scaffold was exploited to design new macrocyclic inhibitors such as [[simeprevir]] (TMC-435) and [[danoprevir]].<ref>{{cite journal | last1 = Chatel-Chaix | first1 = L | last2 = Baril | first2 = M | last3 = Lamarre | first3 = D | title = Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel | journal = Viruses | date = August 2010 | volume = 2 | issue = 8 | pages = 1752–65 | doi = 10.3390/v2081752 | pmid = 21994705 | pmc = 3185733}}</ref>
Its development was halted in phase Ib clinical trials because of toxicity in animals. However, ciluprevir scaffold was exploited to design new macrocyclic inhibitors such as [[simeprevir]] (TMC-435) and [[danoprevir]].<ref>{{cite journal | vauthors = Chatel-Chaix L, Baril M, Lamarre D | title = Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel | journal = Viruses | volume = 2 | issue = 8 | pages = 1752–65 | date = August 2010 | pmid = 21994705 | pmc = 3185733 | doi = 10.3390/v2081752 | doi-access = free }}</ref>


==References==
== References ==
{{reflist}}
{{reflist}}


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[[Category:Abandoned drugs]]
[[Category:Abandoned drugs]]
[[Category:NS3/4A protease inhibitors]]
[[Category:NS3/4A protease inhibitors]]



{{antiinfective-drug-stub}}
{{antiinfective-drug-stub}}

Latest revision as of 23:58, 3 April 2023

Ciluprevir
Clinical data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
  • Development terminated
Pharmacokinetic data
Protein binding>99.1%[1]
Identifiers
  • (2R,6S,12Z,13aS,14aR,16aS)-6-[(Cyclopentyloxycarbonyl)amino]-2-({7-methoxy-2-[(propan-2-ylamino)-1,3-thiazol-4-yl]quinolin- 4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a] [1,4]diazacyclopentadecine-14a(5H)-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC40H50N6O8S
Molar mass774.93 g·mol−1
3D model (JSmol)
  • O=C2N[C@]7(C(=O)O)C[C@H]7/C=C\CCCCC[C@H](NC(=O)OC1CCCC1)C(=O)N6[C@H]2C[C@@H](Oc3cc(nc4c3ccc(OC)c4)c5nc(sc5)NC(C)C)C6
  • InChI=1S/C40H50N6O8S/c1-23(2)41-38-43-32(22-55-38)31-19-34(28-16-15-26(52-3)17-30(28)42-31)53-27-18-33-35(47)45-40(37(49)50)20-24(40)11-7-5-4-6-8-14-29(36(48)46(33)21-27)44-39(51)54-25-12-9-10-13-25/h7,11,15-17,19,22-25,27,29,33H,4-6,8-10,12-14,18,20-21H2,1-3H3,(H,41,43)(H,44,51)(H,45,47)(H,49,50)/b11-7-/t24-,27-,29+,33+,40-/m1/s1
  • Key:PJZPDFUUXKKDNB-KNINVFKUSA-N

Ciluprevir was a drug used experimentally in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim and developed under the research code of BILN 2061. It was the first-in-class NS3/4A protease inhibitor to enter clinical development and tested in human.[2] Ciluprevir is a potent competitive reversible inhibitor of NS3/4A protease from HCV genotype 1a (Ki = 0.3 nM) and 1b (Ki = 0.66 nM). It shows good selectivity for NS3 protease against representative serine and cysteine proteases, human leukocyte elastase and cathepsin B (IC50 > 30 μM).[1]

Its development was halted in phase Ib clinical trials because of toxicity in animals. However, ciluprevir scaffold was exploited to design new macrocyclic inhibitors such as simeprevir (TMC-435) and danoprevir.[3]

References[edit]

  1. ^ a b Tan SL, He Y, eds. (2011). Hepatitis C: Antiviral Drug Discovery and Development. Norfolk, UK: Caister Academic Press. p. 199. ISBN 978-1-904455-78-3.
  2. ^ Tan SL (2006). "6. HCV NS3-4A Serine Protease". In Tan SL (ed.). Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk (UK): Horizon Bioscience. ISBN 978-1-904933-20-5. PMID 21250377.
  3. ^ Chatel-Chaix L, Baril M, Lamarre D (August 2010). "Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel". Viruses. 2 (8): 1752–65. doi:10.3390/v2081752. PMC 3185733. PMID 21994705.
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