title: Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).
abstract: A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile.
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: xiang-yang.ye@bms.com.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Ye
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: David
authors.initials: D
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Stephanie Y
authors.initials: SY
authors.lastname: Chen
authors.affiliation: CADD, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Akbar
authors.initials: A
authors.lastname: Nayeem
authors.affiliation: Lead Evaluation, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.affiliation: Lead Evaluation, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.affiliation: MAP, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: MAP, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Harper
authors.affiliation: BDAS, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Bogdan G
authors.initials: BG
authors.lastname: Sleczka
authors.affiliation: BDAS, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.affiliation: BDAS, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Kirby
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: Jeffrey.robl@bms.com.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013777:Tetrazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D000218:Adamantane
keywords: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1); Enzyme inhibitor; Structure–activity relationships (SAR)