An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent, United Kingdom. paul.stupple@pfizer.com
Paul A
PA
Stupple
David V
DV
Batchelor
Martin
M
Corless
Patrick K
PK
Dorr
David
D
Ellis
David R
DR
Fenwick
Sébastien R G
SR
Galan
Rhys M
RM
Jones
Helen J
HJ
Mason
Donald S
DS
Middleton
Manos
M
Perros
Francesca
F
Perruccio
Michelle Y
MY
Platts
David C
DC
Pryde
Deborah
D
Rodrigues
Nicholas N
NN
Smith
Peter T
PT
Stephenson
Robert
R
Webster
Mike
M
Westby
Anthony
A
Wood
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D006224:Cricetinae; D003510:Cyclohexanes / Q000494:pharmacology; D004285:Dogs; D024882:Drug Resistance, Viral; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D000077592:Maraviroc; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology; D014326:Tropanes
D019380:Anti-HIV Agents; D053961:Azabicyclo Compounds; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C000606913:KCNH2 protein, human; D014230:Triazoles; D014326:Tropanes; C530956:PF 232798; D000077592:Maraviroc