title: 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.
authors.affiliation: Department of Chemical Research, Sigma Tau Pharmaceutical Industries S.p.A., Via Pontina Km 30.400, 00040 Pomezia, Italy. fabio.giannessi@sigma-tau.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Giannessi
authors.forename: Pompeo
authors.initials: P
authors.lastname: Pessotto
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tassoni
authors.forename: Piero
authors.initials: P
authors.lastname: Chiodi
authors.forename: Roberto
authors.initials: R
authors.lastname: Conti
authors.forename: Francesco
authors.initials: F
authors.lastname: De Angelis
authors.forename: Natalina
authors.initials: N
authors.lastname: Dell'Uomo
authors.forename: Roberto
authors.initials: R
authors.lastname: Catini
authors.forename: Roberto
authors.initials: R
authors.lastname: Deias
authors.forename: Maria Ornella
authors.initials: MO
authors.lastname: Tinti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Arduino
authors.initials: A
authors.lastname: Arduini
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002087:Butyrates / Q000138:chemical synthesis* / Q000494:pharmacology; D002331:Carnitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005215:Fasting; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007662:Ketosis / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C470759:4-trimethylammonio-3-((tetradecylcarbamoyl)amino)butyrate; D001786:Blood Glucose; D002087:Butyrates; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D000644:Quaternary Ammonium Compounds; C026968:oleoylcarnitine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine; D020155:3-Hydroxybutyric Acid