Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors
| Autor: | Bin Liu, Gary D. Lopaschuk, Thomas Arrhenius, Steven Brown, Charles Harmon, Rick L. Barr, David Wallace, Vicki Thorn, Jason R.B. Dyck, Jie-Fei Cheng, Souvothy Tith, Sean Reily, Mi Chen, Masayuki Haramura, Chi Ching Mak, Alex M. Nadzan |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Carboxy-lyases Carboxy-Lyases Swine Coenzyme A Morpholines Allosteric regulation Myocardial Ischemia In Vitro Techniques Rats Sprague-Dawley chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Animals Carnitine Beta oxidation chemistry.chemical_classification biology Myocardium Phenylurea Compounds Fatty Acids Malonyl-CoA decarboxylase Rats Malonyl Coenzyme A Enzyme Glucose chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Energy Metabolism Oxidation-Reduction medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 49(5) |
| ISSN: | 0022-2623 |
| Popis: | The discovery and structure−activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I), a key enzyme for mitochondrial fatty acid oxidation. As a result of the increase in malonyl-CoA levels, fatty acid oxidation rates were decreased and the glucose oxidation rates were significantly increased. Demonstration of in vivo efficacy of methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate (6u) in a pig ischemia model indicated that MCD inhibitors may be useful for treating ischemic heart diseases. |
| Databáze: | OpenAIRE |
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