Reversible Carnitine Palmitoyltransferase Inhibitors with Broad Chemical Diversity as Potential Antidiabetic Agents

Abstract

A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.

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

“…In J Med Chem [12] we published a paper where we demonstrated in intact rat liver mitochondria the highest activity (IC(50) = 0.7 microM) for a compound belonging to the derived class of "carnitine analogues with long alkyl chain". In enzymatic inhibition tests, carried out in liver and heart mitochondria this compound also showed a good selectivity (M-CPT1/L-CPT1 IC(50) ratio = 4.86) for CPT1 between liver and heart isoform.…”

Synthesis and antibacterial, antifungal activity of N-(4-fluorophenyl)-N-carboxyethylaminothiazole derivatives

“…25 The formed sodium salts were convertefd into acids by acidifying the reaction mixture with acetic acid to pH 6. The structures of the synthesized compounds were confirmed on the basis of their IR, (17) was obtained from compound 1 and 50% aqueous chloroacetaldehyde in refluxing water. The obtained water-soluble amino acid hydrochloride was transformed into amino acid by adding sodium acetate to the reaction mixture.…”

“…Thiazoles are found to be associated with various biological activities such as antiviral, 1 antimicrobial, 25 antifungal, 6 anticancer, 7 anti-inflammatory, 8,9 antihypertensive, 10,11 anti-HIV, 1214 anticoagulant and antiarrhythmic, 15 antidepressant, 16 antidiabetic, 17 etc. Chalcones have been shown to exhibit diverse biological activity, including antibacterial, antileishmalian, antimaliar, antifungal, antiviral, antifilarial, anti-inflammatory activities.…”

An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine

“…[25Ϫ34] Among them, phosphocarnitine (2), an analogue in which the carboxy group has been replaced with a phosphoryl residue, has recently been obtained. [35] Recent reports on the synthesis and biological activity of several structurally diversified carnitine analogues including phosphonates [36] and Bakers yeast reduction of 3-substituted 2-oxopropylphosphonates [37] has prompted us to disclose a new method for the preparation of (S)-2 based on Jacobsen's hydrolytic kinetic resolution (HKR) of the racemic epoxyphosphonate 3. In this paper we give a full account of our synthesis of optically active (S)-3 [38] and describe its transformation into phosphocarnitine (S)-2.…”