5QII

CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-(3-(1-(4-CHLOROPHENYL)CYCLOPROPYL) -[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-8-YL)PROPAN-2-OL

Summary for 5QII

• Entry DOI: 10.2210/pdb5qii/pdb
• Group deposition: 11betaHSD1 (G_1002051)
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-{3-[1-(4-chlorophenyl)cyclopropyl][1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol, ... (4 entities in total)
• Functional Keywords: 11b-hsd1, sdr, dehydrogenase, hydroxysteroid, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 129670.24

Authors

Sheriff, S. (deposition date: 2018-07-03, release date: 2018-12-19, Last modification date: 2024-03-06)

Primary citation

Li, J.,Kennedy, L.J.,Walker, S.J.,Wang, H.,Li, J.J.,Hong, Z.,O'Connor, S.P.,Ye, X.Y.,Chen, S.,Wu, S.,Yoon, D.S.,Nayeem, A.,Camac, D.M.,Ramamurthy, V.,Morin, P.E.,Sheriff, S.,Wang, M.,Harper, T.W.,Golla, R.,Seethala, R.,Harrity, T.,Ponticiello, R.P.,Morgan, N.N.,Taylor, J.R.,Zebo, R.,Maxwell, B.,Moulin, F.,Gordon, D.A.,Robl, J.A.
Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD-1).
ACS Med Chem Lett, 9:1170-1174, 2018

PubMed Abstract: BMS-823778 (), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED = 34 mg/kg). Compound also showed excellent inhibition in an adipose DIO mouse model (ED = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

PubMed: 30613321
DOI: 10.1021/acsmedchemlett.8b00307

Experimental method

X-RAY DIFFRACTION (2.45 Å)