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  • br Conclusions GPCRs are versatile


    Conclusions GPCRs are versatile signaling molecules regulating almost all physiological processes, including energy homeostasis and glucose homeostasis.105, 106 They also prove to be important therapeutic targets. Drugs targeting GPCRs account for 30% of current pharmaceutical sales. GPR40 is a member of family A GPCRs. Since the deorphanization of GPR40 in 2003, various functions of GPR40 have been identified and characterized, including insulin secretion, incretin secretion, glucagon secretion, immune inflammation, bone density, neurogenesis, pain control, taste preference, and cell proliferation. Tremendous progress has been made on the development of GPR40 agonists in the treatment of T2DM, and most importantly, one of these ligands, TAK-875, has been successfully tried in phase II clinical trials. However, our understanding of some functions of GPR40 and the underlying mechanisms are still controversial and incomplete. Further studies are warranted to address these questions.
    Introduction Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin deficiency and insulin resistance, often accompanied by multiple complications such as cardiovascular disease, renal failure and retinopathy. Currently, the most common oral antidiabetic agents include sulfonylureas, metformin, glitazones, all of which are associated with limited efficacy and adverse side effects [1], [2]. There are only a few insulin secretagogues with low risk of hypoglycemia and weight gain, such as DPP-IV inhibitors, SGLT2 inhibitors and GLP-1 agonists [3], [4]. The urgent need for novel oral antidiabetic agents with sustained safety and efficacy stimulates efforts to develop new mechanisms to improve glycemic control. GPR40 (also known as FFAR1) has, since its deorphanization as a cell surface free fatty acids receptor in 2003, become an attractive and potential target for T2DM therapy [5], [6], [7]. GPR40 is a G-protein-coupled receptor, highly expressed in pancreatic β-cells and intestinal enteroendocrine sq 22 [8]. Activation of GPR40 by medium (C6C12) to long (C14C24) chain saturated and unsaturated fatty acids enhances glucose-stimulated insulin secretion (GSIS). However, mechanisms of the activation of GPR40 to GSIS are only partially understood and remain to be fully explained. Several studies have pointed that GPR40 is coupled with heterotrimeric G protein Gαq/11, which activates phospholipase C, leading to the formation of diacylglycerol (DAG) and inositol-triphosphate (IP3). IP3 binding to its receptor on endoplasmatic reticulum activates an intracellular Ca2+ mobilization. The generation of DAG stimulates protein kinase D1 and promotes F-Actin polymerization. Subsequently, both Ca2+ mobilization and F-Actin polymerization enhance insulin secretion [9], [10]. The modulation of insulin secretion via GPR40 is dependent on glucose concentration, indicating GPR40 agonists could have a low risk of hypoglycemia. A variety of synthetic GPR40 agonists containing 3-phenylpropanoic acid and its bioisostere have been reported (Fig. 1) [11], [12], [13], [14]. Among these potent molecules, TAK-875, developed from a modification of compound 1, was the most advanced in clinical phase III. TAK-875 showed significant glycemic control and ideal pharmacokinetics profiles. The dihydrobenzofuran ring of TAK-875 is highly resistant to β-oxidation, thus slowing down its rate of metabolism [15], [16], [17]. Unfortunately, the development of TAK-875 was terminated by Takeda due to liver toxicity in December 2013 [18]. The modification of TAK-875 from compound 1 inspired us to choose compound 1 as a starting structure to explore novel GPR40 agonists in a different way. It has been recognized that GPR40 is expressed in the brain. While the consequences of activation of GPR40 in the brain have not been identified [19], [20]. A recent study found a GPR40 agonist (AM-3189) with high topological polar surface area (tPSA) showed minimal CNS penetration. tPSA is defined as the surface area occupied by nitrogen and oxygen atoms, and polar hydrogens bonded to these heteroatoms [21]. It is a novel parameter associated with incidence of toxicity for highly lipophilic and low polarity compounds. To avoid potential effects in central nervous system, we decided to improve tPSA by introducing functional groups with greater tPSA to compound 1, which has a high lipophilicity by itself [22], [23]. Compared with compound 1, the replacement of the 2,6-dimethylphenyl group with 3,5-dimethylisoxazole in compound 11a led to a noticeable increase in the tPSA [24]. The well-known rule of five describes clog P should less than 5. For GPR40 agonists, strict range of cLog P has not been proposed as far. However, a high cLog P value is related with undesirable ADMET properties [25]. Most of GPR40 agonists present cLog P values between 4 and 5. We considered this range was probably ideal and the value of compound 1 (cLog P = 6.16) was too high. The introduction of 3,5-dimethylisoxazole also decreased cLog P. Based on compound 11a, we designed and synthesized a series of compounds containing 3,5-dimethylisoxazole. On the one hand, we introduced halogen, alkyl or alkoxyl on the phenyl to obtain compound 11b–l and 22a–h. On the other hand, we replaced phenyl with pyridyl to obtain compound 28a–d[26], [27], [28]. TUG-770 is a highly potent GPR40 agonist with favorable physicochemical and pharmacokinetic properties [29]. The introduction of the ethynyl connecting the phenyl rings is very successful. Comparing the size of compound 11a and TAK-875, we thought 11a was shorter. So we decided to introduce the ethynyl into compound 36 to make the 3,5-dimethylisoxazole closer to the solvent region. Most of these compounds were proved to be novel GPR40 agonist by biological evaluation in vitro and in vivo, along with optimized tPSA and cLog P. Among them, compound 11k was found to be the most efficacious in vitro and in vivo as a promising lead compound.