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Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4 0 -(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (()-1. An efficient and scalable synthesis of (()-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum's acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step SuzukiÀMiyaura couplingÀbromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.

AMG 837 (1) is a novel GPR40 agonist selected for clinical development for the treatment of type 2 diabetes. A lysine salt was initially identified as a development form. However, due to the poor crystallinity and severe hygroscopicity of this form, investigations on the free acid form of the drug substance and salt screening were conducted to identify an acceptable physical form for long-term development. A sodium and calcium salt were identified as potentially viable phases, and polymorph screening was conducted on both. The quality attributes of the salts were then compared to determine which phase would be preferred for development.

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The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = −78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2–5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.