Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

被引：22

作者：

Hoyt, Scott B. ^{[1
]}

Park, Min K. ^{[1
]}

London, Clare ^{[1
]}

Xiong, Yusheng ^{[1
]}

Tata, Jim ^{[1
]}

Bennett, D. Jonathan ^{[2
]}

Cooke, Andrew ^{[2
]}

Cai, Jiaqiang ^{[2
]}

Carswell, Emma ^{[2
]}

Robinson, John ^{[2
]}

MacLean, John ^{[2
]}

Brown, Lindsay ^{[2
]}

Belshaw, Simone ^{[2
]}

Clarkson, Thomas R. ^{[2
]}

Liu, Kun ^{[1
]}

Liang, Gui-Bai ^{[1
]}

Struthers, Mary ^{[1
]}

Cully, Doris ^{[1
]}

Wisniewski, Tom ^{[1
]}

Ren, Ning ^{[1
]}

Bopp, Charlene ^{[1
]}

Sok, Andrea ^{[1
]}

Cai, Tian-Quan ^{[1
]}

Stribling, Sloan ^{[1
]}

Pai, Lee-Yuh ^{[1
]}

Ma, Xiuying ^{[1
]}

Metzger, Joe ^{[1
]}

Verras, Andreas ^{[1
]}

McMasters, Daniel ^{[1
]}

Chen, Qing ^{[1
]}

Tung, Elaine ^{[1
]}

Tang, Wei ^{[1
]}

Salituro, Gino ^{[1
]}

Buist, Nicole ^{[1
]}

Kuethe, Jeff ^{[1
]}

Rivera, Nelo ^{[1
]}

Clemas, Joe ^{[1
]}

Zhou, Gaochao ^{[1
]}

Gibson, Jack ^{[1
]}

Maxwell, Carrie Ann ^{[1
]}

Lassman, Mike ^{[1
]}

McLaughlin, Theresa ^{[1
]}

Castro-Perez, Jose ^{[1
]}

Szeto, Daphne ^{[1
]}

Forrest, Gail ^{[1
]}

Hajdu, Richard ^{[1
]}

Rosenbach, Mark ^{[1
]}

Ali, Amjad ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

[2] Merck Res Labs, Newhouse ML1 5SH, Lanark, Scotland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 05期

关键词：

aldosterone synthase; CYP11B2; hypertension; ALDOSTERONE SYNTHASE INHIBITORS; HYPERTENSION; DISEASE;

D O I：

10.1021/acsmedchemlett.5b00054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

引用

页码：573 / 578

页数：6

共 16 条

[1] Aldosterone synthase inhibition in humans
Azizi, Michel
Amar, Laurence
Menard, Joel
[J]. NEPHROLOGY DIALYSIS TRANSPLANTATION, 2013, 28 (01) : 36 - 43
[2] Rhesus monkey model for concurrent analyses of in vivo selectivity, pharmacokinetics and pharmacodynamics of aldosterone synthase inhibitors
Cai, Tian-Quan
Stribling, Sloan
Tong, Xinchun
Xu, Ling
Wisniewski, Thomas
Fontenot, Jane A.
Struthers, Mary
Akinsanya, Karen O.
[J]. JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 2015, 71 : 137 - 146
[3] Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension Results of a Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Trial
Calhoun, David A.
White, William B.
Krum, Henry
Guo, Weinong
Bermann, Georgina
Trapani, Angelo
Lefkowitz, Martin P.
Menard, Joel
[J]. CIRCULATION, 2011, 124 (18) : 1945 - U124
[4] Aldosterone and cardiovascular disease
Carey, Robert M.
[J]. CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY, 2010, 17 (03) : 194 - 198
[5] Cerny MA, 2013, CURR TOP MED CHEM, V13, P1385
[6] Aldosterone and inflammation
Gilbert, Kimberly C.
Brown, Nancy J.
[J]. CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY, 2010, 17 (03) : 199 - 204
[7] Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascular and Renal Diseases
Hu, Qingzhong
Yin, Lina
Hartmann, Rolf W.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (12) : 5011 - 5022
[8] Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats
Huang, Bing S.
White, Roselyn A.
Jeng, Arco Y.
Leenen, Frans H. H.
[J]. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2009, 296 (04) : R994 - R1000
[9] Coexpression of CYP11B2 or CYP11B1 with adrenodoxin and adrenodoxin reductase for assessing the potency and selectivity of aldosterone synthase inhibitors
LaSala, Daniel
Shibanaka, Yasuhiko
Jeng, Arco Y.
[J]. ANALYTICAL BIOCHEMISTRY, 2009, 394 (01) : 56 - 61
[10] The influence of drug-like concepts on decision-making in medicinal chemistry
Leeson, Paul D.
Springthorpe, Brian
[J]. NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (11) : 881 - 890

← 1 2 →