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Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.
Authors
Staas DD, Bell IM, Burgey CS, Deng JZ, Gallicchio SN, Lim JJ, Paone DV, Potteiger CM, Shaw AW, Stevenson H, Stump CA, Blair Zartman C, Moore EL, Bruno JG, Mosser SD, White RB, Kane SA, Salvatore CA, Graham SL, Williams TM, Selnick HG, Fraley MEAbstract
A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.