Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders

被引：14
|
作者：
Yoon, David S. [1 ]
Wu, Shung C. [1 ]
Seethala, Ramakrishna [2 ]
Golla, Rajasree [2 ]
Nayeem, Akbar [3 ]
Everlof, John G. [4 ]
Gordon, David A. [5 ]
Hamann, Lawrence G. [1 ]
Robl, Jeffrey A. [1 ]
机构：
[1] Bristol Myers Squibb Co, Res & Dev, Dept Chem, Princeton, NJ 08543 USA
[2] Bristol Myers Squibb Co, Res & Dev, Lead Evaluat, Princeton, NJ 08543 USA
[3] Bristol Myers Squibb Co, Res & Dev, CADD, Princeton, NJ 08543 USA
[4] Bristol Myers Squibb Co, Res & Dev, PCO Discovery Pharmaceut, Princeton, NJ 08543 USA
[5] Bristol Myers Squibb Co, Res & Dev, Dept Biol, Princeton, NJ 08543 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 21期
关键词：
11-Beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1); Enzyme inhibitor; Pyridyl sulfonamide; Type-2; diabetes; SELECTIVE INHIBITORS; VISCERAL OBESITY; POTENT; HYPERGLYCEMIA; DESIGN; MODEL; MICE;
D O I：
10.1016/j.bmcl.2014.09.012
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11 beta-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5045 / 5049
页数：5
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