PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

DESCRIPTION provided by applicant The goal of the proposed Phase II SBIR is to advance a novel class of alpha beta nicotinic acetylcholine receptor antagonists new molecular entities which show excellent in vivo efficacy in blocking nicotine self administratio and reinstatement of nicotine seeking towards development as smoking cessation therapy We have discovered a series of highly potent alpha beta nAChR functional antagonists all of which have single digit nanomolar binding affinity and andgt fold target selectivity versus the closely related and nAChR subtypes In our successful Phase I effort we showed that three lead compounds from this series not only significantly block nicotine self administration in rats at low doses without effect on food responding but also block reinstatement of nicotine seeking an animal model of relapse The significant efficacy of these selective alpha beta nAChR ligands strongly suggests that alpha beta nAChR functional antagonismandapos is a promising pharmacological mechanism for smoking cessation pharmacotherapy We have achieved all of the Aims of our Phase I SBIR and conducted additional studies to support the suitability of this class of compounds for further drug development We now seek Phase II support to advance an optimized set of lead candidates through a series of andapos de riskingandapos experiments with the goal of selecting a andapos development candidateandapos for the proposed indication smoking cessation A second goal is to position at least one other compound in our series as backup for the same indication or as a future development candidate for other indications In Aim we will scale up non GMP a panel of optimized alpha beta nAChR ligands for preformulation and development activities In Aim the development candidates will be characterized in a series of ADME studies and PK in two species In Aim confirmation of oral efficacy of the selected candidates will be determined in a rat model of nicotine self administration and reinstatement of nicotine seeking In Aim we will carry out detailed safety pharmacology and early toxicology studies including GLP cardiovascular safety for dog functional observational battery and Range finding toxicology in two species The desired outcome of this project will be the selection of the most suitable andapos development candidateandapos which will be immediately ready for definitive GLP toxicology studies for an IND submission and advancement as smoking cessation pharmacotherapy PUBLIC HEALTH RELEVANCE The overall goal of the proposed research is to advance the development of novel smoking cessation medications This project is of high significance because these potent lead compounds are targeted to a subtype of the nicotinic receptors that have been genetically associated with increased smoking behavior and inability to quit These new drug candidates have shown superior efficacy in inhibiting nicotine self administration and relapse in animal models attesting to the genetic association studies that this nicotinic receptor subtype indeed plays a role in addiction to nicotine These drug candidates represent a new approach for smoking cessation aids that are urgently needed given that the current repertoire of cessation aids are besieged with black box warnings We seek to continue the development of this novel class of drug candidates into safe and effective medications for smoking cessation and maintaining abstinence