title: Design and synthesis of novel imidazoline derivatives with potent antihyperglycemic activity in a rat model of type 2 diabetes.
abstract: Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(alpha-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg(-1), without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity.
authors.affiliation: Université Toulouse III, Faculté des Sciences Pharmaceutiques, Laboratoire de Chimie Pharmaceutique, F-31062 Toulouse Cedex 09, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Crane
authors.forename: Maria
authors.initials: M
authors.lastname: Anastassiadou
authors.forename: Salomé
authors.initials: S
authors.lastname: El Hage
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Stigliani
authors.forename: Geneviève
authors.initials: G
authors.lastname: Baziard-Mouysset
authors.forename: Marc
authors.initials: M
authors.lastname: Payard
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Leger
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Bizot-Espiard
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002417:Cattle; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D013311:Streptozocin; C029899:imidazole