Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type II Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4‘,5‘-dihydro-1‘H- imidazol-2‘-yl)piperazines and Isosteric Analogues of Imidazoline

Abstract

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazines resulted in the identification of 1-methyl-4-(2′,4′-dichlorobenzyl)-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of R 2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4′,5′-dihydro-1′H-imidazol-2′-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 µmol/kg) as after ip administration and appears as a good candidate for clinical investigations.

Current Therapies and Emerging Targets for the Treatment of Diabetes

“…S-22068 (8) has a potent effect on glucose tolerance and increased significantly insulin secretion in diabetic rats [28]. Unlike earlier imidazoline-based secretagogues, 8 does not have a high affinity for α-2 adrenoceptors or the known imidazoline binding sites I 1 or I 2 , but may act through a novel imidazoline-binding site.…”

Glucose-induced insulin secretion is potentiated by a new imidazoline compound

“…However, the blockade of α 2 -adrenoceptors is not responsible for the insulin secretion because some α 2 -adrenoceptor blocking agents are without any influence on insulin release. The imidazoline moiety of the compound seems to be responsible for the insulin release (Le Bihan et al 1999). The effects of the α 2 -adrenoceptor antagonist SL84.0418, an imidazoline derivative, and its two enantiomers deriglidole and SL86.0714 on glucose and insulin levels have been examined in healthy mice and diabetic rats.…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…S-22068 has a potent effect on glucose tolerance and significantly increased insulin secretion in diabetic rats (Pelé-Tounian et al, 1998;Le Bihan et al, 1999). Unlike earlier imidazoline-based secretagogs, this compound does not have a high affinity for ␣ 2 -adrenoceptors or the imidazoline binding sites I 1 or I 2 but may act through a as-yet-unrecognized imidazoline-binding site.…”