Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

Abstract

A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methylthiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC 50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.Key words Takeda G-protein-coupled receptor 5 agonist; bioisostere; microsomal clearance; structureactivity relationship Takeda G-protein-coupled receptor 5 (TGR5), also known as G-protein coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor responsive to bile acids. It has been found to be ubiquitously expressed in animal and human tissues, including the liver, intestine, heart, spleen, skeletal muscle, brown adipose tissue, gallbladder and brain. [1][2][3][4] It is thought to play an important role in the regulation of energy homeostasis and glucose metabolism. Activation of the TGR5 receptor by bile acids triggers an increase in energy expenditure in brown adipose tissue and skeletal muscle.5) More importantly, TGR5 activation also promotes glucagon-like peptide-1 (GLP-1) secretion in the intestine. 6) As a member of the incretin family, GLP-1 acts as an important physiological regulator in glucose control via several mechanisms of action.7) But endogenous GLP-1 is significantly limited as a direct drug for the treatment of type 2 diabetes because of its rapid inactivation in plasma by dipeptidyl peptidase-4 (DPP-4). There are two main classes of alternative GLP-1-based drugs being widely used in a clinical setting: DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. 8) However, these drugs may not be able to halt the progression of type 2 diabetes because they all exert their actions through increasing the plasma concentration of "GLP-1R agonists," and they thus may lack some of the local actions that endogenous GLP-1 is likely to have. 9)Therefore, a novel therapy that stimulates endogenous GLP-1 secretion by TGR5 agonists is considered as a superior alternative for the treatment of type 2 diabetes mellitus.In recent years, many different kinds of TGR5 agonists have been reported (Fig. 1). Structurally, TGR5 agonists can fall into two categories. The first category is bile acid derivatives, [10][11][12] such as lithocholic acid (LCA) and 6α-ethyl-23(S)-methylcholic acid (INT-777). The second category is non-bile acid derivatives, including naturally occurring non-bile acid agonists such as oleanolic acid and betulinic acid, 13,14) and synthetic small molecular TGR5 agonists. [15][16][17][18][19][20][21][22] However, only one ...

Constructing 4-hydroxythiazole-5-carboxamide building blocks in one pot

“…4-Hydroxythiazole-5-carboxamide has attracted rising attention recently, owing to the discovery that compounds with this motif show significant activity as transient receptor potential cation channel subfamily M member 8 (TRPM8) antagonists, 1,2 proteasome inhibitors, 3 antifungal succinate dehydrogenase Inhibitors, 4 11-hydroxysteroid dehydrogenase Type I inhibitors, 5 GSK-3 inhibitors, 6 et al All these drug targets are directly related with somatic pain and ocular pain, 1 inflammation, ischemia, cancer, 3,7 obesity, 5,8 neurodegenerative disease 9,10 treatment. For example, 2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxamide 1,11 (1) (Figure 1) is reported to be a selective antagonist of TRPM8, 4-hydroxy-2-(pyridin-4yl)thiazole-5-carboxamide (2) an inhibitor of the serine/threonine protein kinase Cdc7 in cancer cells.…”

“…7 Also, 4phenoxythiazol-5-carboxamides were developed into highly potent TGR5 ( Takeda G-protein-coupled receptor 5)agonist，represented by (4-cyclopropyl-3,4-dihydro-1(2H)-quinoxalinyl) [4-(2,6-dichlorophenoxy)-2-methyl-5-thiazolyl]methanone (3) the EC50 of hTGR5 is 1.1 nm. 8 2-[2-(Cyclopropanecarbonylamino)pyridin-4yl]-4-(cyclopropylmethoxy)-1,3-thiazole-5-carboxamide (4, thiazolylpyridines) emerges as a highly selective GSK-3 inhibitor. 6 Besides as drug candidates, 4-hydroxythiazole-5-carboxamides are also found in antifungal succinate dehydrogenase inhibitors as potential novel fungicide candidates.…”