Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

Abstract

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl) acetamide (4g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)-aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with functional selectivity over the β1-and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.Key words β3-adrenergic receptor; agonist; 2-aminothiazole; phenoxypropanolamine; diabetes A major increase in the prevalence of obesity, non-insulin dependent (type 2) diabetes and related cardiovascular disorders has led to the search for new pharmacological approaches in the treatment of these conditions. 1,2) In the 1980s and 1990s, the β3-adrenergic receptor (AR) was identified as a possible therapeutic target for the treatment of type 2 diabetes and obesity.3,4) Early potent and selective β3-AR agonists, such as BRL- 37344 5) and CL-316243, 6) were reported to be effective anti-obesity and anti-diabetic agents in rodents 7) ( Fig. 1). Human clinical trials with these agents for use in treating metabolic disorders, however, have been disappointing due to a lack of efficacy or an unfavorable side-effect profile. 8,9) The clinical failure of such compounds has been attributed to a lack of sufficient β3-AR potency and selectivity relative to β1-and β2-ARs resulting from pharmacologic differences between rodent and human receptors, a notion supported by the discovery, cloning, and characterization of the human, rat, and mouse β3-ARs. [10][11][12] Recent studies have indicated that, in addition to adipocytes, the β3-AR is also distributed in human urinary bladder detrusor tissue and its relaxation occurs mainly via β3-AR. [13][14][15] (Fig. 1). The availability of appropriate human receptors has facilitated the design and synthesis of a new generation of highly potent β3-AR agonists. Subtype selectivity for β3-AR agonists must be kept specifically in mind, since activation of the β1-or β2-ARs could lead to undesirable side effects such as increased heart rate or muscle tremors.We previously described efforts in this area that included the disclosure of acetanilide-based phenylethanolamine 1, which showed potent β3-AR agonistic activity with functional selectivity over β1-and β2-ARs and oral hypoglycemic activity in diabetic kk mice. 20) Given our assumption that the (2-aminothiazol-4-yl) acetamide moiety of 1 might be a favorable pharmaocophore for β3-AR agonistic activity and selectivity, we decided to apply this structure part in the phenoxypropanolamine analogue instead of the phenylethanolamine one. We therefore synthesized simple N-phenyl-(2-aminot...

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles

“…To achieve β3 adrenergic selectivity, the insertion of bulky groups on the right-hand side (RHS) of the molecule is favorable ( Figure 1 ). However, since the approval of mirabegron in 2012, few selective agonist compounds for the β3-AR receptor have been reported [ 13 , 14 , 15 ]. Selective β3 adrenergic agonists include CL 316,243 [ 16 ], amibegron (SR58611A) [ 17 , 18 ], mirabegron (YM-178) [ 10 ], and vibegron (RVT-901) [ 19 ] ( Figure 1 ).…”