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Papers of the Week

Papers: 1 May 2021 - 7 May 2021

Pharmacology/Drug Development


2021 Apr 28

Bioorg Med Chem Lett

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists: Heterocyclic Modification of a Novel Azepinone Lead.


Luo G, Jiang X-J, Chen L, Conway CM, Gulianello M, Kostich W, Keavy D, Signor LJ, Chen P, Davis C, Whiterock VJ, Schartman R, Widmann KA, Macor JE, Dubowchik GM
Bioorg Med Chem Lett. 2021 Apr 28:128077.
PMID: 33932522.


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.