Novel macrocyclic inhibitors of hepatitis C NS3/4A protease featuring a 2-amino-1,3-thiazole as a P4 carbamate replacement.
Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.
Di Francesco
M Emilia
ME
Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy. mariaemilia_difrancesco@merck.com
Dessole
Gabriella
G
Nizi
Emanuela
E
Pace
Paola
P
Koch
Uwe
U
Fiore
Fabrizio
F
Pesci
Silvia
S
Di Muzio
Jillian
J
Monteagudo
Edith
E
Rowley
Michael
M
Summa
Vincenzo
V
D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D004285:Dogs; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013844:Thiazoles / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002219:Carbamates; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus