New fatty acid oxidation inhibitors with increased potency lacking adverse metabolic and electrophysiological properties.
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.
Koltun
Dmitry O
DO
Department of Bioorganic Chemistry, 3172 Porter Dr., Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com
Marquart
Timothy A
TA
Shenk
Kevin D
KD
Elzein
Elfatih
E
Li
Yuan
Y
Nguyen
Marie
M
Kerwar
Suresh
S
Zeng
Dewan
D
Chu
Nancy
N
Soohoo
Daniel
D
Hao
Jia
J
Maydanik
Victoria Y
VY
Lustig
David A
DA
Ng
Khing Jow
KJ
Fraser
Heather
H
Zablocki
Jeffery A
JA
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
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