Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys.
Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyl-transferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of > or = 70%, as measured by beta-hydroxybutyrate levels, the end product of beta-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of beta-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.
Deems
R O
RO
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Anderson
R C
RC
Foley
J E
JE
D020155:3-Hydroxybutyric Acid; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006885:Hydroxybutyrates / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D063065:Organophosphonates / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D007328:Insulin; D063065:Organophosphonates; D002334:Carnitine O-Palmitoyltransferase; C110822:SDZ CPI 975; D020155:3-Hydroxybutyric Acid