Maria Ornella Tinti

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

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.

Lyotropic mesomorphism of alkyl esters of acyl-L-carnitines

Abstract The lyotropic polymorphism of a series of alkyl esters of acyl-L-carnitine has been studied by optical polarizing microscopy and X-ray diffraction. The different structures observed as a function of concentration and temperature have been characterized and their topology determined. As a result, two different phase sequence patterns have been detected: esters of normal alcohols bearing an alkyl chain of 6 or more carbon atoms in the acyl substituent display only a lamellar phase, while compounds which bear a relatively short alkyl chain (4 or less carbon atoms) show in addition non-lamellar type I hexagonal and cubic Q230 phases. From the analysis of the areas-per-molecule at the polar/apolar interface, the ability of the compounds investigated to form not only non-lamellar phases, but also direct micelles in isotropic solution has been related to the structural characteristics of the molecules. Curved, convex interfaces (in micelles and in non-lamellar phases) are possible only for the most pola...

Inversion of Configuration of (S)‐β‐Hydroxy‐γ‐butyrolactone with Total Retention of the Enantiomeric Purity

In this paper we report the inversion of configuration of (S)-β-hydroxy-γ-butyrolactone [(S)-1] to its (R) enantiomer (R)-1, with total retention of the enantiomeric purity, by a four-step procedure. The (R)-β-hydroxy-γ-butyrolactone [(R)-1] was thus synthetized with an overall chemical yield of 47% and > 97% ee. This transformation opens an economic route to the production of (R)-GABOB and (R)-carnitine, among other biologically active compounds, from a D-hexose source, or, alternatively, from the industrial waste compound (S)-carnitine. During the reaction sequence, the intermediate β-lactone 4 is also prepared, which is now under investigation as a chiral synthon for new synthetic applications.

2-{3-[2-(4-chlorophenyl)ethoxy]-phenylthio}-2-methylpropanoic acid : a fibrate-like compound with hypolipidemic and antidiabetic activity

Diabetes is a complex metabolic disease which has reached epidemic proportions; its continuously increasing incidence is a consequence of the excessive caloric intake and lack of physical activity that characterize the western lifestyle. The progressive impairment of insulin sensitivity and eventual deterioration of b-cell function are the underlying causes of the overt disease. The classical and commonly used treatments for lowering glycemia are the insulin secretagogues, such as the sulfonylureas, and metformin, an insulin sensitizer with a mechanism of action that is still under investigation. In recent years rosiglitazone and pioglitazone have entered the market as insulin sensitizers and anti-hyperglycemic drugs. They are representatives of the new thiazolidinedione (TDZ) class of agents, which elicit their effects through activation of the g isoform of the nuclear peroxisome proliferator-activated receptor (PPARg). 6] The activity of TDZs in humans is accompanied by weight gain and risk of edema, whereas the liver toxicity observed with troglitazone, the first marketed (and soon thereafter withdrawn) representative of this family, seems to be more the result of its particular chemical structure than of its TDZ class-related mechanism of action. Despite an improvement in the ability to control glycemia, the prevention and management of the negative cardiovascular aspects of the disease remain the focus of open primary research, as such aspects rank diabetes the fourth leading cause of mortality in developed countries. In this context, a drug that is able to effectively correct dyslipidemia as well as hyperglycemia and insulin sensitivity is certainly of great interest. Fibrates such as fenofibrate and bezafibrate have been widely used for decades as hypolipidemic, antiatherosclerotic, and cardioprotective agents, and are known to act through the activation of the a isoform of PPAR (PPARa). For these reasons, compounds that activate both PPARa and PPARg receptors (PPARa/g mixed agonists) are considered to be very promising targets (ref. [15] and references therein), but only a few of them bear fibrate-related structures. In the last few years, new hypolipidemic PPARa agonists with improved potency and selectivity have also appeared, such as GW9578 and its closely related analogue GW7647, both of which are characterized by a thioisobutyrate moiety. During our search for new hypolipidemic and anti-hyperglycemic agents, we found quite unexpectedly that compound 3 (Scheme 1), which is structurally related to the fibrates, considerably improves diabetic conditions in C57BL/KsJ db/db diabetic mice (Table 1). In particular, the decrease in glucose level was similar to that effected by rosiglitazone, even if 3 was administered at a higher dose (25 instead of 5 mgkg , twice a day by oral gavage for 25 days), with greatly improved homogeneity of values. This last point should not be underestimated, as in our experience, not all animals in experimental groups respond to rosiglitazone and similar compounds. The same has also been reported in studies with humans. In an oral glucose tolerance test (OGTT) after 19 days of treatment, the glycemic area under curve (AUC) was considerably lower in the case of 3 with respect to control and fibrate results, and [a] Dr. F. Giannessi Department of Endocrinology and Metabolism Sigma-Tau S.p.A Via Pontina km 30400, 00040 Pomezia, Rome (Italy) Fax: (+39)06-9139-3988 E-mail : fabio.giannessi@sigma-tau.it [b] Prof. F. De Angelis Department of Chemistry, Chemical Engineering, and Materials University of L’Aquila, Coppito, 67010 L’Aquila (Italy) Fax: (+39)0862-433753 E-mail : deangeli@univaq.it [c] Dr. N. Dell’Uomo, Dr. E. Tassoni, Dr. T. Brunetti, Dr. M. O. Tinti Department of Chemical Research Sigma-Tau S.p.A (Italy) [d] Dr. P. Pessotto, Dr. A. F. Sciarroni, Dr. F. M. Milazzo, A. Peschechera Department of Endocrinology and Metabolism Sigma-Tau S.p.A (Italy) [e] Dr. P. Carminati Director of Research & Development Department Sigma-Tau S.p.A (Italy) Supporting information for this article is available on the WWW under http://www.chemmedchem.org or from the author.

QSAR of a Series of Carnitine Acetyl Transferase (CAT) Substrates

Carnitine acyl transferases are a family of enzymes that differ with respect to subcellular localization and substrate specificity. Carnitine acetyl transferase (CAT) is mainly found in the mitochondrial matrix where it is postulated to play a key role in stabilizing the CoA-SH/CoA-SAc ratio.1 CAT catalyses the reversible reaction:

Novel 7-Oxyiminomethyl Derivatives of Camptothecin with Potent in Vitro and in Vivo Antitumor Activity

Acetyl - L - carnitine + Coa - SH \leftrightarrow L - carnitine + acetyl - Coa

Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity.

that has an equilibrium constant equal to 0.6. The kinetic enzymatic mechanism for CAT follows a random-order equilibrium reaction where Michaelis constant (K m ) approximates true dissociation constant (K s ) and binding of one substrate has little or no effect on binding of the second.2 The aim of this work is to study a set of acyl-CoA derivatives that includes linear, branched and cycloalkyl, and unsaturated substituents 2,3,4 A QSAR approach is used to investigate the influence of such substituents on kinetic parameters, K m and V’max.

Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase

Alzheimer’s disease (AD), the most common form of dementia in elderly people, is characterized by the extracellular deposition of 39–43 amino acid peptide referred as amyloid β-peptide (Aβ). The mechanism by which Aβ elicits its toxicity is poorly understood, however the aggregation of the peptide into fibrils has emerged as a major factor in Aβ toxicity.1