molecules of the month

DS-3801b is a non-macrolide GPR38 agonist and a Ph. I clinical candidate for treatment of chronic constipation (SAD 1-100 mg PO). GPR38 is the receptor for the GI hormone motilin, which as the name suggests, regulates GI motility. Agonism of GPR38 is expected to reduce constipation by activating GI tract smooth muscle cells to move things along. DS-3801b was found to be safe and well tolerated after doses up to 50 mg, with mild GI adverse events. The molecule was optimized from a previously disclosed GPR38 agonist, and has significantly greater sp3 character than its starting point. Though the side chains are similar, there was a dramatic core change. A “magic methyl” effect was also observed by installing a methyl…