ABSTRACT
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.
Subject(s)
Amides/pharmacology , Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinsic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC50 in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.
Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Transient Receptor Potential Channels/antagonists & inhibitors , Animals , Biological Transport, Active , CHO Cells , Calcium Channels , Cricetulus , Dogs , Dose-Response Relationship, Drug , Drug Discovery , High-Throughput Screening Assays , Humans , In Vitro Techniques , Madin Darby Canine Kidney Cells , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Pain Measurement/drug effects , Rats , Structure-Activity Relationship , TRPA1 Cation ChannelABSTRACT
A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.
