title: The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors.
abstract: 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.
authors.affiliation: Pfizer Global Research & Development, La Jolla Labs, 10770 Science Center Drive, San Diego, CA 92121, United States. henry.cheng@pfizer.com
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Jacqui
authors.initials: J
authors.lastname: Hoffman
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Sajiv K
authors.initials: SK
authors.lastname: Nair
authors.forename: Stephan
authors.initials: S
authors.lastname: Cripps
authors.forename: Jean
authors.initials: J
authors.lastname: Matthews
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.forename: Michele
authors.initials: M
authors.lastname: Yang
authors.forename: Stan
authors.initials: S
authors.lastname: Kupchinsky
authors.forename: Klaus
authors.initials: K
authors.lastname: Dress
authors.forename: Martin
authors.initials: M
authors.lastname: Edwards
authors.forename: Bridget
authors.initials: B
authors.lastname: Cole
authors.forename: Evan
authors.initials: E
authors.lastname: Walters
authors.forename: Christine
authors.initials: C
authors.lastname: Loh
authors.forename: Jacques
authors.initials: J
authors.lastname: Ermolieff
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.forename: Ganesh B
authors.initials: GB
authors.lastname: Bhat
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Herrera
authors.forename: Tom
authors.initials: T
authors.lastname: Pauly
authors.forename: Natilie
authors.initials: N
authors.lastname: Hosea
authors.forename: Genevieve
authors.initials: G
authors.lastname: Paderes
authors.forename: Paul
authors.initials: P
authors.lastname: Rejto
mesh_terms: 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
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C551005:PF 877423; D011759:Pyrrolidines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C032519:pyrrolidine; D000218:Adamantane