2. Academic Validation
  3. 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

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

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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