Design, synthesis, and SAR studies of novel polycyclic acids as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 22, 2011, Pages 6699-6704

  Ye, Xiang Yang ^a   Chen, Stephanie Y ^a   Nayeem, Akbar ^a   Golla, Rajasree ^a   Seethala, Ramakrishna ^a   Wang, Mengmeng ^a,b   Harper, Timothy ^a   Sleczka, Bogdan G ^a   Li, Yi Xin ^a   He, Bin ^a   Kirby, Mark ^a   Gordon, David A ^a   Robl, Jeffrey A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b PFIZER INC   (United States)

Author keywords

11 Hydroxysteroid dehydrogenase type 1; Inhibitor; Polycyclic acids

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; [2,2,1] BICYCLOHEPTANE; [3,2,1] BICYCLOOCTANE; BENZENE DERIVATIVE; C 2 4 F PHENYL DERIVATIVE; CARBOXYLIC ACID; CYCLOHEXYL DERIVATIVE; POLYCYCLIC CARBOXYLIC ACID; UNCLASSIFIED DRUG;

ARTICLE; DRUG DESIGN; DRUG SYNTHESIS; HUMAN; MOUSE; NONHUMAN;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ACETIC ACID; ACIDS; ADAMANTANE; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; PROTEIN BINDING; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80054748382     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.09.055     Document Type: Article

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29. Though the attempts to grow co-crystal structure of ligands 4-6 with human 11β-HSD-1 failed, we did obtain several co-crystal structures of their corresponding amide derivatives bound to human 11β-HSD-1. The conformation of adamantyl moiety and carbonyl group in co-crystal structures are superimposed to those shown in docking model (Fig. 3). The results will be reported elsewhere.
30. The software used for docking is Glide-SP implemented in Maestro version 9.0; http://www.schrodinger.com.
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37. In general, the higher potency of the inhibitors for the human enzyme versus the mouse can be attributed to the higher lipophilic nature of the binding pocket of human 11β-HSD-1. Significant differences in the binding pocket include, A226 and Y177 in human versus E226 and Q177 in mouse. The docking model (Fig. 3) shows the adamantyl group pointing towards Y177 in human, but Q177 in mouse, and the 4-F-phenyl group pointing towards A226 in human, but E226 in mouse. In both cases, the interaction of the ligand with the human enzyme is more favored than with the mouse enzyme. This difference can be especially dependent upon the chemotype. For example, see our recent publication in Ref. 7a.
38. In general, compounds in Tables 1 and 2 were generated via the reaction sequences in Scheme 1 using different ketones 7 as the starting material and appropriate RMgX or RLi as the nucleophile. Some acids in Table 1 require additional steps for functional group transformation. For typical experimental procedure, see Supplementary data.
39. Compound 6w was synthesized from compound 6v. See Supplementary data for details.
40. 50 values in the biochemical assay.
41. Though not reported, all inhibitors tested exhibited little/no inhibition (<50% at 10 μM) versus human 11β-HSD-2.
42. The lipophilic nature of these carboxylic acids resulted in a concern for PPAR activity. We tested several compounds from this class, including 4a, and no PPAR activity across α, γ, δ subtypes was detected up to a concentration of 30 μM.