title: 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.
authors.affiliation: Departments of Chemical Research, Endocrinology & Metabolism, and Analytical Research, Sigma Tau Pharmaceutical Industries S.p.A., Via Pontina Km 30.400, 00040 Pomezia, Italy. fabio.giannessi@sigma-tau.it
authors.forename: F
authors.initials: F
authors.lastname: Giannessi
authors.forename: P
authors.initials: P
authors.lastname: Chiodi
authors.forename: M
authors.initials: M
authors.lastname: Marzi
authors.forename: P
authors.initials: P
authors.lastname: Minetti
authors.forename: P
authors.initials: P
authors.lastname: Pessotto
authors.forename: F
authors.initials: F
authors.lastname: De Angelis
authors.forename: E
authors.initials: E
authors.lastname: Tassoni
authors.forename: R
authors.initials: R
authors.lastname: Conti
authors.forename: F
authors.initials: F
authors.lastname: Giorgi
authors.forename: M
authors.initials: M
authors.lastname: Mabilia
authors.forename: N
authors.initials: N
authors.lastname: Dell'Uomo
authors.forename: S
authors.initials: S
authors.lastname: Muck
authors.forename: M O
authors.initials: MO
authors.lastname: Tinti
authors.forename: P
authors.initials: P
authors.lastname: Carminati
authors.forename: A
authors.initials: A
authors.lastname: Arduini
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine; D020155:3-Hydroxybutyric Acid