Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor.
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.
Li
Hui
H
Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. hui.li@pfizer.com
Tatlock
John
J
Linton
Angelica
A
Gonzalez
Javier
J
Jewell
Tanya
T
Patel
Leena
L
Ludlum
Sarah
S
Drowns
Matthew
M
Rahavendran
Sadayappan V
SV
Skor
Heather
H
Hunter
Robert
R
Shi
Stephanie T
ST
Herlihy
Koleen J
KJ
Parge
Hans
H
Hickey
Michael
M
Yu
Xiu
X
Chau
Fannie
F
Nonomiya
Jim
J
Lewis
Cristina
C
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004285:Dogs; D016174:Hepacivirus / Q000201:enzymology*; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011753:Pyrones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines
D000998:Antiviral Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011753:Pyrones; D012324:RNA-Dependent RNA Polymerase; D014230:Triazoles; C550357:filibuvir; D011743:Pyrimidines