Discovery of potent and orally available malonyl- CoA decarboxylase inhibitors as cardioprotective agents

被引：42

作者：

Cheng, Jie-Fei

Huang, Yujin

Penuliar, Richard

Nishimoto, Masahiro

Liu, Larry

Arrhenius, Thomas

Yang, Guang

O'Leary, Eoin

Barbosa, Miguel

Barr, Rick

Dyck, Jason R. B.

Lopaschuk, Gary D.

Nadzan, Alex M.

机构：

[1] Chugai Pharma USA, LLC, Dept Chem, San Diego, CA 92121 USA

[2] Chugai Pharma USA, LLC, Dept Discovery Biol, San Diego, CA 92121 USA

[3] Univ Alberta, Metab Modulator Res Ltd, MMRL, Res Transit Facil 2020, Edmonton, AB, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 14期

关键词：

D O I：

10.1021/jm0605029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido) butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.

引用

页码：4055 / 4058

页数：4

共 41 条

[1] Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle [J].

Alam, N ;

Saggerson, ED .

BIOCHEMICAL JOURNAL, 1998, 334 :233-241

[2]

Anderson Joe R, 2005, Cardiol Rev, V13, P202, DOI 10.1097/01.crd.0000161979.62749.e7

[3]

BARR R, 1997, MEASUREMENT CARDIOVA, P19

[4] Fatty acid metabolism is enhanced in type 2 diabetic hearts [J].

Carley, AN ;

Severson, DL .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2005, 1734 (02) :112-126

[5] Design and synthesis of heterocyclic malonyl-CoA decarboxylase inhibitors [J].

Cheng, JF ;

Chen, M ;

Liu, B ;

Hou, Z ;

Arrhenius, T ;

Nadzan, AM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (03) :695-700

[6] Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors [J].

Cheng, Jie-Fei ;

Mak, Chi Ching ;

Huang, Yujin ;

Penuliar, Richard ;

Nishimoto, Masahiro ;

Zhang, Lin ;

Chen, Mi ;

Wallace, David ;

Arrhenius, Thomas ;

Chu, Donald ;

Yang, Guang ;

Barbosa, Miguel ;

Barr, Rick ;

Dyck, Jason R. B. ;

Lopaschuk, Gary D. ;

Nadzan, Alex M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (13) :3484-3488

[7] Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation [J].

Dyck, JRB ;

Cheng, JF ;

Stanley, WC ;

Barr, R ;

Chandler, MP ;

Brown, S ;

Wallace, D ;

Arrhenius, T ;

Harmon, C ;

Yang, G ;

Nadzan, AM ;

Lopaschuk, GD .

CIRCULATION RESEARCH, 2004, 94 (09) :E78-E84

[8] Characterization of cardiac malonyl-CoA decarboxylase and its putative role in regulating fatty acid oxidation [J].

Dyck, JRB ;

Barr, AJ ;

Barr, RL ;

Kolattukudy, PE ;

Lopaschuk, GD .

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1998, 275 (06) :H2122-H2129

[9] The molecular basis of malonyl-CoA decarboxylase deficiency [J].

FitzPatrick, DR ;

Hill, A ;

Tolmie, JL ;

Thorburn, DR ;

Christodoulou, L .

AMERICAN JOURNAL OF HUMAN GENETICS, 1999, 65 (02) :318-326

[10]

Gao JM, 1999, J LIPID RES, V40, P178

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