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Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44DA036968-02
Agency Tracking Number: R44DA036968
Amount: $997,167.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIDA
Solicitation Number: PA14-071
Timeline
Solicitation Year: 2014
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-09-30
Award End Date (Contract End Date): 2019-02-28
Small Business Information
11350 SW VILLAGE PKWY, Port Saint Lucie, FL, 34987-2352
DUNS: 078516360
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 JINHUA WU
 (772) 345-4716
 jwu@tpims.org
Business Contact
 JINHUA WU
Phone: (772) 345-4716
Email: jwu@tpims.org
Research Institution
N/A
Abstract
DESCRIPTION provided by applicant Smoking remains the number one avoidable cause of death in the United States and costs the economy tens of billions of dollars every year Current therapies include nicotine replacement with a patch or gum inhibition of the dopamine system with bupropion and partial activation of the neuronal nicotinic acetylcholine receptor nAChR with varenicline None of these have been particularly effective upon initial use and even in the cases of initial success relapse rates are nearly regardless of the treatment drugs or therapies Additional therapies in clinical trials include the non selective nAChR antagonist mecamylamine nicotine antibodies and behavior modification The nAChR most closely associated with the addictive nature of cigarettes is the nAChR Activation of thi receptor is considered to be the primary mediator of nicotine reward and the selective but low affinity nAChR antagonist DH E has been demonstrated to block nicotine self administration in rodent models However there are very few high affinity and selective antagonists available to examine as smoking cessation medications Starting from a small molecule combinatorial library containing more than million individual compounds we have identified selective nAChR compounds With funding from our Phase I application we have identified lead compounds with very high affinity potency and selectivity both with respect to binding affinity and in vitro functional activity at the nAChR Both of these compounds ae full antagonists at nAChRs One compound has been demonstrated to attenuate nicotine self administration and reinstatement in rats In this Phase II SBIR we propose to optimize our lead compounds to further improve drug like properties while maintaining or improving affinity and selectivity In Specific Aim similar to a traditional drug discovery andquot hit to leadandquot process additional SAR will be conducted to improve the PK PD properties of our current lead compounds This aim will include medicinal chemistry and coupled with in vitro affinity and efficacy testing along with the pharmacological profiling to identify drug like compounds Specific Aim will be similar to the andquot lead to developmentandquot process within drug discovery in which selected high affinity and selective antagonists will be tested in a battery of in vitro and n vivo assays to determine oral bioavailability stability blood brain barrier penetration pharmacokinetics and hERG inhibition In addition to determining in vivo efficacy for ability to block nicotine self administration and reinstatement in rats this aim will include the determination of additional pharmacological effects on locomotion anxiety depression and reward aversion in order to choose compounds to move forward to future IND enabling toxicology PUBLIC HEALTH RELEVANCE Smoking is by far the number one avoidable cause of death in the United States and is an enormous drain our economy in terms of missed work hospitalization and early death Although smoking cessation medications are available they are in large part marginally successful In this Phase II SBIR we will conduct lead optimization studies on new selective nicotine receptor antagonists to identify lead compounds for IND enabling studies and ultimately test as smoking cessation medications

* Information listed above is at the time of submission. *

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