2. Academic Validation
  3. Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists

Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129944. doi: 10.1016/j.bmcl.2024.129944.
Donnette D Staas 1,  Ian M Bell 2,  Christopher S Burgey 1,  James Z Deng 1,  Steven N Gallicchio 1,  John J Lim 1,  Daniel V Paone 1,  Craig M Potteiger 1,  Anthony W Shaw 1,  Heather Stevenson 1,  Craig A Stump 1,  C Blair Zartman 1,  Eric L Moore 3,  Joseph G Bruno 4,  Scott D Mosser 4,  Rebecca B White 5,  Stefanie A Kane 3,  Christopher A Salvatore 3,  Samuel L Graham 1,  Theresa M Williams 1,  Harold G Selnick 1,  Mark E Fraley 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Merck & Co., Inc., West Point, PA 19486, USA.
  • 2 Department of Discovery Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: ian_bell@merck.com.
  • 3 Department of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
  • 4 Department of In Vitro Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA.
  • 5 Department of Drug Metabolism & Pharmacokinetics, Merck & Co., Inc., West Point, PA 19486, USA.
PMID: 39233187 DOI: 10.1016/j.bmcl.2024.129944
Abstract

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.

Keywords

CGRP receptor antagonist; Calcitonin gene-related peptide; Migraine.

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