title: New fatty acid oxidation inhibitors with increased potency lacking adverse metabolic and electrophysiological properties.
abstract: New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat.
authors.affiliation: Department of Bioorganic Chemistry, 3172 Porter Dr., Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Koltun
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Marquart
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Shenk
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Marie
authors.initials: M
authors.lastname: Nguyen
authors.forename: Suresh
authors.initials: S
authors.lastname: Kerwar
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Nancy
authors.initials: N
authors.lastname: Chu
authors.forename: Daniel
authors.initials: D
authors.lastname: Soohoo
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
authors.forename: Victoria Y
authors.initials: VY
authors.lastname: Maydanik
authors.forename: David A
authors.initials: DA
authors.lastname: Lustig
authors.forename: Khing Jow
authors.initials: KJ
authors.lastname: Ng
authors.forename: Heather
authors.initials: H
authors.lastname: Fraser
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Zablocki
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004355:Drug Stability; D004594:Electrophysiology; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases