1140898-82-3Relevant academic research and scientific papers
Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)
Li, Jun,Kennedy, Lawrence J.,Walker, Steven J.,Wang, Haixia,Li, James J.,Hong, Zhenqiu,O'Connor, Stephen P.,Ye, Xiang-Yang,Chen, Stephanie,Wu, Shung,Yoon, David S.,Nayeem, Akbar,Camac, Daniel M.,Ramamurthy, Vidhyashankar,Morin, Paul E.,Sheriff, Steven,Wang, Mengmeng,Harper, Timothy W.,Golla, Rajasree,Seethala, Ramakrishna,Harrity, Thomas,Ponticiello, Randolph P.,Morgan, Nathan N.,Taylor, Joseph R.,Zebo, Rachel,Maxwell, Brad,Moulin, Frederick,Gordon, David A.,Robl, Jeffrey A.
, p. 1170 - 1174 (2018)
BMS-823778 (2), 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 (IC50 = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 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 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
The syntheses of [14C]BMS-823778 for use in a human ADME clinical study and of [13CD3 13CD2]BMT-094817, a stable-isotope labeled standard of a newly detected human metabolite
Maxwell, Brad D.,Tran, Scott B.,Lago, Michael,Li, Jun,Bonacorsi, Samuel J.
, p. 255 - 259 (2016/05/24)
Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [14C]BMS-823778 was synthesized in two steps from commercially available [2-14C]acetone. The radiochemical purity of the synthesized [14C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity of 7.379 μCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [13CD3 13CD2]BMT-094817 for use as a liquid chromatography/mass spectrometry standard. [13CD3 13CD2]BMT-094817 was prepared in five labeled steps from [13CD3]iodomethane. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of [14C]BMS-823778 for use in a human adsorption, distribution, metabolism, and excretion (ADME) study was required. One result of the ADME study was the detection of a new human metabolite, BMT-094817. [13CD3 13CD2]BMT-094817 was then prepared for use as a liquid chromatography/mass spectrometry standard.
ISOTOPICALLY LABELED TRIAZOLOPYRIDINE 11-BETA HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS
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Page/Page column 17; 21, (2015/05/06)
Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds of formula I: or stereoisomers or pharmaceutically acceptable salts thereof, wherein R* is an isotopically labeled hydroxypropyl moiety.
Optimization of 1,2,4-triazolopyridines as inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)
Li, Jun,Kennedy, Lawrence J.,Wang, Haixia,Li, James J.,Walker, Steven J.,Hong, Zhenqiu,Oconnor, Stephen P.,Nayeem, Akbar,Camac, Daniel M.,Morin, Paul E.,Sheriff, Steven,Wang, Mengmeng,Harper, Timothy,Golla, Rajasree,Seethala, Ramakrishna,Harrity, Thomas,Ponticiello, Randolph P.,Morgan, Nathan N.,Taylor, Joseph R.,Zebo, Rachel,Gordon, David A.,Robl, Jeffrey A.
supporting information, p. 803 - 808 (2014/08/05)
Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β- hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.
TRIAZOLOPYRIDINE 11-BETA HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS
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Page/Page column 24, (2009/04/24)
Novel compounds are provided which are 11 -beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxyster
