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
  • 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: [email protected].
  • 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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