Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase.
We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.
Stansfield
Ian
I
Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy. ian_stansfield@merck.com
Ercolani
Caterina
C
Mackay
Angela
A
Conte
Immacolata
I
Pompei
Marco
M
Koch
Uwe
U
Gennari
Nadia
N
Giuliano
Claudio
C
Rowley
Michael
M
Narjes
Frank
F
D000495:Allosteric Site; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000737:chemistry; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D004791:Enzyme Inhibitors; D007211:Indoles; D009584:Nitrogen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase