Novel inhibitors of fatty acid oxidation as potential metabolic modulators.
We describe the synthesis of novel inhibitors of fatty acid oxidation as potential metabolic modulators for the treatment of stable angina. Replacement of the 2H-benzo[d]1,3-dioxolene ring system in our initial lead 3 with different benzthiazoles, benzoxazoles and introducing small alkyl substituents into the piperazine ring resulted in analogues with enhanced inhibitory activity against 1-(14)[C]-palmitoyl-CoA oxidation in isolated rat heart mitochondria (6, IC(50)=70 nM; 25, IC(50)=23 nM).
Elzein
Elfatih
E
Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. elfatih.elzein@cvt.com
Shenk
Kevin
K
Ibrahim
Prabha
P
Marquart
Tim
T
Kerwar
Suresh
S
Meyer
Stephanie
S
Ahmed
Hiba
H
Zeng
Dewan
D
Chu
Nancy
N
Soohoo
Daniel
D
Wong
Shirley
S
Leung
Kwan
K
Zablocki
Jeff
J
D000818:Animals; D004852:Epoxy Compounds / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D004852:Epoxy Compounds; D005227:Fatty Acids; D010171:Palmitoyl Coenzyme A