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

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.

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

“…Another compound we tested in experimental diabetes, an ureidic derivative from class of "carnitine analogues with long alkyl chain". This ureidic compound, with extraordinarily high selectivity toward the liver CPT1 isoform with respect to the heart isoform was able to reduce serum glucose levels in diabetic db/db mice treated orally for 45 days at a dose of 50 mg/kg twice a day, showing also an antiketotic activity in normal fasted rats and therefore selected for development as a potential antiketotic and antidiabetic drug [13].…”

Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias

“…ST1326 was initially selected by Sigma-Tau laboratories as a candidate for diabetes and ketoacidosis therapy. 13,14 Results reported by Pacilli et al 15 demonstrated that the pharmacologic inhibition of FAO by ST1326 impairs cancer cell survival and inhibits tumor cell proliferation in in vitro and in vivo models of Burkitt lymphoma. Therefore, in this study we aimed to expand this approach, investigating the in vitro antileukemic activity of ST1326 on human leukemia cell lines and primary cells obtained from patients with different hematologic diseases.…”

A reversible carnitine palmitoyltransferase (CPT1) inhibitor offsets the proliferation of chronic lymphocytic leukemia cells

“…A reversible CPT1A inhibitor, (R)-N-(tetradecylcarbamoyl)-aminocarnitine (ST1326) developed initially for diabetes treatment (6,7), was shown to decrease lymphoma (8) and leukemia (9) cell growth in preclinical studies. Though, no information is available on its effects to activated/proliferating CLL cells.…”