Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease.
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Andrews
David M
DM
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. david.m.andrews@gsk.com
Carey
Seb J
SJ
Chaignot
Helene
H
Coomber
Barry A
BA
Gray
Norman M
NM
Hind
S Lucy
SL
Jones
Paul S
PS
Mills
Gail
G
Robinson
J Ed
JE
Slater
Martin J
MJ
D002460:Cell Line; D015195:Drug Design; D004355:Drug Stability; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D012697:Serine Endopeptidases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D007769:Lactams; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases