Discovery of a Long-Chain Carbamoyl Aminocarnitine Derivative, a Reversible Carnitine Palmitoyltransferase Inhibitor with Antiketotic and Antidiabetic Activity

Citations Over TimeTop 23% of 2002 papers

Abstract

The synthesis and pharmacological activity of reversible CPT I inhibitors as potential antiketotic and antidiabetic drugs are reported. Such inhibitors constitute a series of enantiomerically pure aminocarnitine derivatives having the general formula (CH3)3N+CH2CH(ZR)CH2COO- (with Z = ureido, carbamate, sulfonamide, and sulfamide moieties; R = C7-C14 linear alkyl chains). A primary pharmacological screening based on the evaluation of CPT I activity in intact rat liver (L-CPT I) mitochondria revealed the best activity for the (R) forms of ureidic derivative 17 (ZR = NHCONHR, R = C14), sulfonamidic derivative 7 (ZR = NHSO2R, R = C12), and sulfamidic derivative 9 (ZR = NHSO2NHR, R = C11). The IC50 values are 1.1, 0.7, and 0.8 microM, respectively. For the carbamic derivative 11 (ZR = NHCOOR, R = C8), an IC50 of 9.5 microM was observed. In addition, an extraordinarily high selectivity toward the liver isoform with respect to the heart isoform (muscle-CPT I identical with M-CPT I) was found for the ureidic compound 17 (IC50(M-CPT I) vs IC50(L-CPTI) = 39.4), as well as for other ureidic or carbamic compounds. Diabetic db/db mice treated orally with 17 and 7 for 45 days at a dose of 50 mg/kg twice a day showed a good reduction of serum glucose levels with respect to the untreated db/db mice (p < 0.01). In addition, 17 showed antiketotic activity in normal fasted rats. 17 has been selected for development as a potential antiketotic and antidiabetic drug.

Related Papers

• → Comparison of Sulfamate and Sulfamide Groups for the Inhibition of Carbonic Anhydrase-II by Using Topiramate as a Structural Platform(2004)53 cited
• → Borylierung von Sulfamiden, Sulfoniminen und Sulfondiiminen/Borylation of Sulfamides, Sulfonimines and Sulfonediimines(1989)7 cited
• → Vibrational spectra of sulfamide and some silver(I)-sulfamides in the 700–150 cm−1 region(1982)4 cited
• [Physical chemistry of combinations with sulfamide bases. Antipyrine-sulfamide combinations].(1984)
• → ChemInform Abstract: Reactivity of Malononitrile Towards Sulfamide and N‐Substituted Sulfamides: Synthesis and Hydrolysis Reactions of 3,5‐Diamino‐1,2,6‐thiadiazine 1,1‐Dioxides.(1988)