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.
Giannessi
F
F
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
Chiodi
P
P
Marzi
M
M
Minetti
P
P
Pessotto
P
P
De Angelis
F
F
Tassoni
E
E
Conti
R
R
Giorgi
F
F
Mabilia
M
M
Dell'Uomo
N
N
Muck
S
S
Tinti
M O
MO
Carminati
P
P
Arduini
A
A
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
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine; D020155:3-Hydroxybutyric Acid