61291-97-2

Upstream product

• 619-55-6 para-methylbenzamide 
• 2362-62-1 4-methylthiobenzamide 
• 61291-92-7 (4-methyl-2-p-tolyl-thiazol-5-yl)-methanol 
• 54001-09-1 ethyl 4-methyl-2-(p-tolyl)thiazole-5-carboxylate 

Downstream Products

• 950505-35-8 7-((4-methyl-2-p-tolylthiazol-5-yl)methoxy)-2H-chromen-2-one 
• 950505-42-7 C₂HF₃O₂*C₂₅H₂₅NO₄S 
• 950505-39-2 (E)-methyl 3-(2-(2-bromoallyloxy)-4-((4-methyl-2-p-tolylthiazol-5-yl)methoxy)phenyl)acrylate 
• 950505-37-0 (E)-methyl 3-(2-hydroxy-4-((4-methyl-2-p-tolylthiazol-5-yl)methoxy)phenyl)acrylate 

Relevant academic research and scientific papers

Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.

Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

BICYCLIC CARBOXYLIC ACID DERIVATIVES USEFUL FOR TREATING METABOLIC DISORDERS

Compounds having the general formula I and/or the general formula II are useful, for example, for treating metabolic disorders in a subject formula (I) (II) where the variables are provided herein. Compositions and methods for using the compounds for preparing medicaments and for treating metabolic disorders such as, for instance, type II diabetes are disclosed.

Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders

The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula [in-line-formulae]Q-L1-P-L2-M-X-L3-A [/in-line-formulae] wherein the definitions of