Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead
| Autor: | Valerie J. Whiterock, Xiang-Jun Jiang, Guanglin Luo, Carl D. Davis, Charles M. Conway, Deborah Keavy, Kimberly A. Widmann, Laura J. Signor, Walter Kostich, Ling Chen, John E. Macor, Gene M. Dubowchik, Richard Schartman, Ping Chen, Michael Gulianello |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Pharmacology Calcitonin gene-related peptide 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Calcitonin Gene-Related Peptide Receptor Antagonists In vivo biology.animal Drug Discovery Humans Molecular Biology CGRP receptor G protein-coupled receptor Indazole Dose-Response Relationship Drug Molecular Structure biology CYP3A4 010405 organic chemistry Organic Chemistry Marmoset Azepines 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry chemistry Molecular Medicine Receptors Calcitonin Gene-Related Peptide |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 43:128077 |
| ISSN: | 0960-894X |
| Popis: | In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect