Molecular Design, Synthesis, and Hypoglycemic Activity of a Series of Thiazolidine-2,4-diones

Abstract

A series of imidazopyridine thiazolidine-2,4-diones were designed and synthesized from their corresponding pyridines. These compounds represent conformationally restricted analogues of the novel hypoglycemic compound rosiglitazone (5). The series was evaluated for its effect on insulin-induced 3T3-L1 adipocyte differentiation in vitro and its hypoglycemic activity in the genetically diabetic KK mouse in vivo. The structure-activity relationships are discussed. On the basis of the in vivo potency, 5-[4-(5-methoxy-3-methyl-3H-imidazo[4, 5-b]pyridin-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (19a) was selected as the candidate for further studies in a clinical setting.

Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

“…The analytical data of the synthesized oxyiminoacetic acids (7,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) are shown in Table 1.…”

“…Many companies are still endeavoring to find a new glucose lowering agent. [23][24][25][26][27][28][29][30][31][32][33][34][35] Although the precise mechanism of action of these drugs remains unknown, recent study suggests that antidiabetic thiazolidinediones interact with a family of nuclear receptors known as peroxisome proliferator-activated receptor (PPAR)-g. 36) PPARg is one of a subfamily of PPARs encoded by independent genes. Three human PPARs, designated PPARa, PPARg, and PPARd, have been identified to date.…”

Stereoselective annelation of 3-substituted imidazo[4,5-b]pyridines with cyanoacetylenic alcohols and domino rearrangement of the adducts

“…For example, a popular soporific remedy, "Zolpidem" ("Ivadal"), is a functionalized imidazo [1,2-a]pyridine. 2 Among other derivatives of imidazopyridines, are potent nitric-oxide synthase inhibitors of inflammatory diseases, 3 inhibitors of AKT kinase, 4 preventive and/or therapeutic agents for neutrophilic inflammation disease, 5 compounds with tuberculostatic 6 and hypoglycemic 7 activities, angiotensin II receptor antagonists, 8 and anticoccidial agents. 9 A series of imidazo[1,2-a]pyridines bearing sulfonylurea functions exhibit herbicidal activity.…”

A simple synthesis of aminopyridines: use of amides as amine source

“…2 Substituted or unsubstituted aminopyridines are also useful precursors for the synthesis of a variety of heteocyclic compounds possessing a medicinal value. [3][4][5][6][7][8][9] For example, 2-(methylamino)nicotinonitrile or 2-amino-3-nitropyridine was used as a synthetic precursor of 1H,3H-pyrido [2,3-d]pyrimidine-2,4-dione 10 or pyrido [2,3-b] pyrazines 11 and imidazo [4,5-b]pyridines 12 respectively.…”

“…21 In 2004, one of us was involved in the preparation of diethylamino derivative of pyrazolopyrimidine via the reaction of 7-chloro-1,3-dimethyl-5-phenyl-1H-pyrazolo [4,3-d]pyrimidine with DMF in the presence of (PPh 3 ) 4 Pd and Na 2 CO 3 (Scheme 1). 22 Very recently, a palladium catalyzed synthesis of N,N-dimethyl [1,8] naphthyridine-2-amines by facile incorporation of NMe 2 group from DMF has been reported. 23 All these methods however require the use of a base (and/or a catalyst) and only limited studies have been carried out with a very few number of substrates.…”