title: Pyridine amides as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
abstract: Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. haixia.wang@bms.com
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.forename: Zheming
authors.initials: Z
authors.lastname: Ruan
authors.forename: James J
authors.initials: JJ
authors.lastname: Li
authors.forename: Ligaya M
authors.initials: LM
authors.lastname: Simpkins
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Smirk
authors.forename: Shung C
authors.initials: SC
authors.lastname: Wu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hutchins
authors.forename: David S
authors.initials: DS
authors.lastname: Nirschl
authors.forename: Katy
authors.initials: K
authors.lastname: Van Kirk
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cooper
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Mary Ellen K
authors.initials: ME
authors.lastname: Salyan
authors.forename: Akbar
authors.initials: A
authors.lastname: Nayeem
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Brian
authors.initials: B
authors.lastname: Carpenter
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D011725:Pyridines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1