Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors

Jie-Fei Cheng; Chi Ching Mak; Yujin Huang; Richard Penuliar; Masahiro Nishimoto; Lin Zhang; Mi Chen; David Wallace; Thomas Arrhenius; Donald Chu; Guang Yang; Miguel Barbosa; Rick Barr; Jason R B Dyck; Gary D Lopaschuk; Alex M Nadzan

doi:10.1016/j.bmcl.2006.03.100

Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3484-8. doi: 10.1016/j.bmcl.2006.03.100. Epub 2006 Apr 27.

Authors

Jie-Fei Cheng¹, Chi Ching Mak, Yujin Huang, Richard Penuliar, Masahiro Nishimoto, Lin Zhang, Mi Chen, David Wallace, Thomas Arrhenius, Donald Chu, Guang Yang, Miguel Barbosa, Rick Barr, Jason R B Dyck, Gary D Lopaschuk, Alex M Nadzan

Affiliation

¹ Department of Chemistry and Discovery Biology, Chugai Pharma LLC., 6275 Nancy Ridge Dr., San Diego, CA 92121, USA. jcheng@trlusa.com

PMID: 16644218
DOI: 10.1016/j.bmcl.2006.03.100

Abstract

A series of heteroaryl-substituted bis-trifluoromethyl carbinols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some thiazole-based derivatives showed potent in vitro MCD inhibitory activities and significantly increased glucose oxidation rates in isolated working rat hearts.

MeSH terms

Animals
Carboxy-Lyases / antagonists & inhibitors*
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glucose / chemistry
Glucose / metabolism
Heart / drug effects
Heterocyclic Compounds / chemistry*
In Vitro Techniques
Methanol / analogs & derivatives
Methanol / chemical synthesis*
Methanol / pharmacology*
Molecular Structure
Oxidation-Reduction
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Heterocyclic Compounds
Carboxy-Lyases
malonyl-CoA decarboxylase
Glucose
Methanol