The co crystal structure of GPR complexed with

The co-crystal structure of GPR40 complexed with TAK-875 provided precise structural information for the rational design of novel GPR40 agonists. The key interactions between the carboxylate with the residues Arg183, Arg258, Tyr91 and Tyr240 of GPR40 were observed. And Trp174ECL2 was oriented nearly perpendicularly to the plane of the dihydroisobenzofuran ring of TAK-875 where an edge-on interaction was formed (Fig. 3). As the mimics of long-chain fatty acid, the early GPR40 agonists were very lipophilic, e.g. GW9508, 1, and 2 (Fig. 4). Although they exhibited high potency, the high lipophilicity might cause lipotoxicity and off-target effects in CNS [25]. For the more advanced GPR40 agonists, more and more factors of drug-likeness were taken into account, for example, lower lipophilicity, smaller molecular size, improved selectivity and ADMET properties. Accordingly, the chemical exploration on the GPR40 agonists are reviewed below with respect to the druglikeness-based structural evolution. The EC50 values cited for the GPR40 agonists below are determined by calcium flux primary assay, unless otherwise specified. Increasing the polarity: The role of lipophilicity in determining the pre-clinical ADMET properties of drug candidate is of paramount importance [26]. Most of the current GPR40 agonists are somewhat lipophilic, so the efforts to reduce the lipophilicity of GPR40 agonists are prominently observed in the literature and patents. Increasing the polarity of the 961 synthesis is the main strategy to reduce the lipophilicity and thus polar groups or heteroatoms are usually introduced into the agonist prototype. TAK-875 is the most advanced GPR40 agonist developed by Takeda, which was terminated in clinical trials phase III due to concerns about liver safety [27]. However, the R&D course of TAK-875 is representative to outline and guide the design and structural optimization of GPR40 agonists. Therefore, its development procedure is introduced in details here as a case study. Firstly, the Takeda researchers screened a number of fatty acids containing aromatic groups analogous to the endogenous ligands, ending up with a new structure GPR40 agonist having 3-phenylpropanoic acid scaffold. The following structure–activity relationship study and structural modification led to the discovery of lead compound 3 (Fig. 5), via incorporating additional π-π interactions and/or lipophilic interactions with GPR40. Although 3 exhibited potent activity, the benzyloxyphenylpropanoic acid series showed poor PK properties with high clearance and low bioavailability, probably due to the phenylpropanoic acid moiety susceptible to β-oxidation [28]. Therefore, the β-position to the carboxylic function was substituted by small residues, which could also be cyclized to the phenyl ring, to block the β-oxidation and improve the selectivity. Stereochemistry at the β-position was shown to be critical with one enantiomer usually being much more active on the GPR40 receptor. Further chemical modification was performed at the 4′-position of the biphenyl tail which was found to tolerate various functionalities. A hydrophilic sulfonylpropoxy sidechain was introduced to decrease the lipophilicity and improve the PK profile [4]. The (S)-(2,3-dihydrobenzofuran-3-yl)acetic acid-based GPR40 agonist TAK-875 stood out as a drug candidate with high potency (EC50=14nM) (Fig. 5) and favorable PK profiles (half-life: rat, 4.7h; dog, 5.9h; bioavailability: rat, 76%; dog, 92%). Reduced blood glucose and augmented insulin secretion effect were observed during an oral glucose tolerance test in both type 2 diabetic N-streptozotocin (N-STZ) rats and Zucker diabetic fatty (ZDF) rats, when TAK-875 was administered (0.3–3mg/kg) one hour before an oral glucose challenge. TAK-875 was also found to improve hyperglycemia in rats unresponsive to sulfonylureas and act additively with sulfonylureas [29]. Furthermore, as an ago-allosteric modulator with partial FFA1 agonistic activity, TAK-875 was demonstrated to potentiate insulin release cooperatively with free fatty acids in an allosteric manner, and have no effect on GSIS in GPR40-knockout mice [10].