The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors.
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.
Cheng
Hengmiao
H
Pfizer Global Research & Development, La Jolla Labs, 10770 Science Center Drive, San Diego, CA 92121, United States. henry.cheng@pfizer.com
Hoffman
Jacqui
J
Le
Phuong
P
Nair
Sajiv K
SK
Cripps
Stephan
S
Matthews
Jean
J
Smith
Christopher
C
Yang
Michele
M
Kupchinsky
Stan
S
Dress
Klaus
K
Edwards
Martin
M
Cole
Bridget
B
Walters
Evan
E
Loh
Christine
C
Ermolieff
Jacques
J
Fanjul
Andrea
A
Bhat
Ganesh B
GB
Herrera
Jocelyn
J
Pauly
Tom
T
Hosea
Natilie
N
Paderes
Genevieve
G
Rejto
Paul
P
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C551005:PF 877423; D011759:Pyrrolidines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C032519:pyrrolidine; D000218:Adamantane