Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate.
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
Mowbray
Charles E
CE
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. Charles.Mowbray@Pfizer.Com
Burt
Catherine
C
Corbau
Romuald
R
Gayton
Simon
S
Hawes
Michael
M
Perros
Manos
M
Tran
Isabelle
I
Price
David A
DA
Quinton
Faye J
FJ
Selby
Matthew D
MD
Stupple
Paul A
PA
Webster
Rob
R
Wood
Anthony
A
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002460:Cell Line; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; D054303:HIV Reverse Transcriptase