Nerve growth factor (NGF) plays a key role in acute and chronic pain states and acts through tropomyosin-receptor-kinase A (TrkA). Selectively inhibiting TrkA has been demonstrated to reduce pain in animal models, thus leading to development of TrkA inhibitors as potential analgesics. Herein we describe the discovery and optimization of a series of potent, efficacious, orally bioavailable TrkA inhibitors with exquisite selectivity, from lead identification through to IND-enabling tox studies. Challenges involving identifying an allosteric binding mode and optimizing ADME properties to limit CNS exposure will be highlighted.

Discovery and optimization of a series of allosteric TrkA inhibitors for the treatment of pain – path to a clinical candidate

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.