Structure-Based Drug Discovery of N-(( R)-3-(7-Methyl-1 H-indazol-5-yl)-1-oxo-1-((( S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3- d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine

  • J Med Chem. 2020 Jul 23;63(14):7906-7920. doi: 10.1021/acs.jmedchem.0c01003.
Sarah J Bucknell  1 ,  Mark A Ator  2 ,  Alastair J H Brown  1 ,  Jason Brown  1 ,  Andrew D Cansfield  1 ,  Julie E Cansfield  1 ,  John A Christopher  1 ,  Miles Congreve  1 ,  Gabriella Cseke  1 ,  Francesca Deflorian  1 ,  Christopher R Jones  1 ,  Jonathan S Mason  1 ,  M Alistair O'Brien  1 ,  Gregory R Ott  2 ,  Mark Pickworth  1 ,  Stacey M Southall  1
Affiliations
  • 1. Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, U.K.
  • 2. Teva Pharmaceuticals, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
PMID: 32558564 DOI: 10.1021/acs.jmedchem.0c01003
Abstract

Structure-based drug design enabled the discovery of 8, HTL22562, a Calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP Receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.

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