AI Article Synopsis
- * By replacing the indazole ring with different heterocycles, we created new compounds that were effective CGRP receptor antagonists with better oral absorption and less CYP3A4 inhibition.
- * Despite having promising results in inhibiting CGRP-induced activity in tests, overall oral bioavailability of these new compounds is still low, highlighting ongoing challenges in developing effective drugs for this area.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.bmcl.2021.128077 | DOI Listing |
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