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

Sarah J Bucknell; Mark A Ator; Alastair J H Brown; Jason Brown; Andrew D Cansfield; Julie E Cansfield; John A Christopher; Miles Congreve; Gabriella Cseke; Francesca Deflorian; Christopher R Jones; Jonathan S Mason; M Alistair O'Brien; Gregory R Ott; Mark Pickworth; Stacey M Southall

doi:10.1021/acs.jmedchem.0c01003

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. Epub 2020 Jul 8.

Authors

Sarah J Bucknell¹, Mark A Ator², Alastair J H Brown¹, Jason Brown¹, Andrew D Cansfield¹, Julie E Cansfield¹, John A Christopher¹, Miles Congreve¹, Gabriella Cseke¹, Francesca Deflorian¹, Christopher R Jones¹, Jonathan S Mason¹, M Alistair O'Brien¹, Gregory R Ott², Mark Pickworth¹, Stacey M Southall¹

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.

MeSH terms

Animals
Binding Sites
Calcitonin Gene-Related Peptide Receptor Antagonists / chemical synthesis
Calcitonin Gene-Related Peptide Receptor Antagonists / metabolism
Calcitonin Gene-Related Peptide Receptor Antagonists / pharmacology*
Calcitonin Gene-Related Peptide Receptor Antagonists / toxicity
Dogs
Drug Design
Humans
Indazoles / chemical synthesis
Indazoles / metabolism
Indazoles / pharmacology*
Indazoles / toxicity
Macaca fascicularis
Migraine Disorders / drug therapy
Molecular Docking Simulation
Molecular Structure
Rats
Receptors, Calcitonin Gene-Related Peptide / metabolism*
Spiro Compounds / chemical synthesis
Spiro Compounds / metabolism
Spiro Compounds / pharmacology*
Spiro Compounds / toxicity
Structure-Activity Relationship

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
Indazoles
Receptors, Calcitonin Gene-Related Peptide
Spiro Compounds