PF-05089771: A Comprehensive Monograph on a Selective Nav1.7 Inhibitor—From Preclinical Promise to Clinical Discontinuation

Executive Summary

This report provides an exhaustive analysis of the investigational drug PF-05089771, a small molecule developed by Pfizer as a selective inhibitor of the voltage-gated sodium channel Nav1.7. It synthesizes all available information, from its chemical properties and unique mechanism of action to its comprehensive clinical trial program and eventual discontinuation. The narrative critically examines the profound translational disconnect between the compound's exceptional preclinical profile—rooted in strong human genetic validation of its target—and its failure to demonstrate broad analgesic efficacy in major clinical pain populations. Key findings regarding its state-dependent pharmacology, novel binding site on the voltage-sensor domain, interspecies pharmacodynamic differences, and the nuanced results from trials in distinct pain etiologies are detailed. The report culminates in a post-hoc analysis of the program's failure, offering critical perspectives on the challenges facing the development of Nav1.7 inhibitors and the broader field of pain therapeutics.

1.0 Introduction: The Rationale for Targeting Nav1.7 in Pain Therapeutics

1.1 The Role of Voltage-Gated Sodium Channels in Nociception

Voltage-gated sodium (Nav) channels are transmembrane proteins essential for the initiation and propagation of action potentials in excitable cells, including neurons.[1] The channel's pore-forming