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
| Autor: | P. Renard, Jean Jacques Godfroid, J. Huet, B. Pfeiffer, A. Lamouri, X. Wang, S. Lidy, D. Manechez, G. Le Bihan, E. Touboul, Alain Ktorza, Georges Dive, Luc Pénicaud, F. Rondu, A. Pele-Tounian, B. Guardiola-Lemaitre |
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| Rok vydání: | 1999 |
| Předmět: |
Blood Glucose
Male Kidney Cortex Stereochemistry Receptors Drug Drug Evaluation Preclinical Imidazoline receptor In Vitro Techniques Chemical synthesis Piperazines Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Receptors Adrenergic alpha-2 In vivo Insulin Secretion Drug Discovery medicine Animals Homeostasis Hypoglycemic Agents Insulin Moiety Glucose homeostasis Rats Wistar Alkyl Cerebral Cortex chemistry.chemical_classification Glucose tolerance test medicine.diagnostic_test Imidazoles Glucose Tolerance Test Rats Piperazine Diabetes Mellitus Type 2 chemistry Drug Design Molecular Medicine Cattle Imidazoline Receptors Rabbits Injections Intraperitoneal |
| Zdroj: | Journal of Medicinal Chemistry. 42:1587-1603 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm981099b |
| Popis: | 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 alpha2 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 micromol/kg) as after ip administration and appears as a good candidate for clinical investigations. |
| Databáze: | OpenAIRE |
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