The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-β-hydroxylase

被引：11

作者：

Adams, Christopher M. ^{[1
]}

Hu, Chii-Whei ^{[2
]}

Jeng, Arco Y. ^{[2
]}

Karki, Rajeshri ^{[1
]}

Ksander, Gary ^{[1
]}

LaSala, Dan ^{[2
]}

Leung-Chu, Jennifer ^{[2
]}

Liang, Guiqing ^{[1
]}

Liu, Qian ^{[1
]}

Meredith, Erik ^{[1
]}

Rao, Chang ^{[1
]}

Rigel, Dean F. ^{[2
]}

Shi, Jie ^{[1
]}

Smith, Sherri ^{[1
]}

Springer, Clayton ^{[1
]}

Zhang, Chun ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[2] Novartis Inst BioMed Res, Cardiovasc & Metab Dis Area, E Hanover, NJ 07936 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 15期

关键词：

CYP11B2; Aldosterone; CYP11B1; Aldosterone synthase inhibitor; Hypertension; CONGESTIVE-HEART-FAILURE; INTRINSIC CLEARANCE; FADROZOLE; CYP11B2;

D O I：

10.1016/j.bmcl.2010.06.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aldosterone, the final component of the renin-angiotensin-aldosterone system, plays an important role in the pathophysiology of hypertension and congestive heart failure. Aldosterone synthase (CYP11B2) catalyzes the last three steps of aldosterone biosynthesis, and as such appears to be a target for the treatment of these disorders. A sulfonamide-imidazole scaffold has proven to be a potent inhibitor of CYP11B2. Furthermore, this scaffold can achieve high levels of selectivity for CYP11B2 over CYP11B1, a key enzyme in the biosynthesis of cortisol. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：4324 / 4327

页数：4

共 25 条

[1] Evaluation of fluorescence- and mass spectrometry - Based CYP inhibition assays for use in drug discovery [J].

Bell, Leslie ;

Bickford, Shari ;

Nguyen, Phong Hung ;

Wang, Jianling ;

He, Timothy ;

Zhang, Bailin ;

Friche, Yannick ;

Zimmerlin, Alfred ;

Urban, Laszlo ;

Bojanic, Dejan .

JOURNAL OF BIOMOLECULAR SCREENING, 2008, 13 (05) :343-353

[2] The human steroid hydroxylases CYP11B1 and CYP11B2 [J].

Bureik, M ;

Lisurek, M ;

Bernhardt, R .

BIOLOGICAL CHEMISTRY, 2002, 383 (10) :1537-1551

[3]

Chauret N, 1998, DRUG METAB DISPOS, V26, P1

[4]

Fisher MB, 2000, DRUG METAB DISPOS, V28, P560

[5] Discovery of selective CYP11B2 (aldosterone synthase) inhibitors for the therapy of congestive heart failure and myocardial fibrosis [J].

Hartmann, RW ;

Mülller, U ;

Ehmer, PB .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2003, 38 (04) :363-366

[6] Adrenal corticosteroids, their receptors and hypertension [J].

Hu, Xiao ;

Bolten, Charles W. .

DRUG DEVELOPMENT RESEARCH, 2006, 67 (12) :871-883

[7]

Kalvass JC, 2001, DRUG METAB DISPOS, V29, P1332

[8] Aldosterone causes vasoconstriction in coronary arterioles of rats via angiotensin II type-1 receptor: Influence of hypertension [J].

Kushibiki, Motol ;

Yamada, Masahiro ;

Oikawa, Koichi ;

Tomita, Hirofumi ;

Osanai, Tomohiro ;

Okumura, Ken .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2007, 572 (2-3) :182-188

[9] Coexpression of CYP11B2 or CYP11B1 with adrenodoxin and adrenodoxin reductase for assessing the potency and selectivity of aldosterone synthase inhibitors [J].

LaSala, Daniel ;

Shibanaka, Yasuhiko ;

Jeng, Arco Y. .

ANALYTICAL BIOCHEMISTRY, 2009, 394 (01) :56-61

[10] In Vivo Active Aldosterone Synthase Inhibitors with Improved Selectivity: Lead Optimization Providing a Series of Pyridine Substituted 3,4-Dihydro-1H-quinolin-2-one Derivatives [J].

Lucas, Simon ;

Heim, Ralf ;

Ries, Christina ;

Schewe, Katarzyna E. ;

Birk, Barbara ;

Hartmann, Rolf W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (24) :8077-8087

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