Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P₁): Discovery and SAR of a Novel Isoxazole Based Series

Abstract

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo

“…Methyl 5-phenylisoxazole-3-carboxylate 14 is well known 20,21 and was synthesized from acetophenone by a slight modification of literature procedures (see Experimental Methods). Following bromination of the methyl carboxylate 14 , Suzuki couplings of the bromoisoxazole 15 (22) with phenyl-, 3-methoxyphenyl-, and 3-hydroxyphenyl-boronic acids gave the 4,5-diarylisoxazole-3-carboxylates 16 , 23 17 , and 18 . Saponification of these and the isoxazolecarboxylate 14 gave the corresponding carboxylic acids 1 – 4 .…”

An Efficient Scale-Up Synthesis of BMS-520, a Potent and Selective Isoxazole-Containing S1P1 Receptor Agonist

“…The preparation of 1 relied on a convergent synthesis (Scheme ) which required two advanced intermediates, tert -butyl 1-(4-( N ′-hydroxycarbamimidoyl)­benzyl)­azetidine-3-carboxylate 2 and 3-phenyl-4-(trifluoromethyl)­isoxazole-5-carboxylic acid 3 . Amidoxime 2 was prepared from commercially available azetidine-3-carboxylic acid 4 in five linear steps utilizing our external collaborator.…”

“…During our drug discovery program, 1-(4-(5-(3-phenyl-4-(trifluoromethyl)­isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)­benzyl)­azetidine-3-carboxylic acid 1 (BMS-520, Figure ) was identified as a novel isoxazole-based S1P 1 receptor agonist, providing highly potent S1P 1 receptor full agonism with an EC 50 of 0.47 nM and selectivity against the S1P 3 receptor. Based on its in vitro potency and selectivity, PD/PK data, and liability profile; BMS-520 ( 1 ) was selected for further biological evaluation.…”

The synthetic and therapeutic expedition of isoxazole and its analogs

“…Agonism of S1P 1 , in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. Watterson et al (2016) synthesized a series of isoxazoles derived from isoxazole-3-carboxylic acids and isoxazole-5-carboxylic acids to develop selective S1P 1 selective agonists. Compound 104 (Fig.…”