Development of selective Cav3 channel blockers for treatment of neuropathic pain

DESCRIPTION provided by applicant Millions of Americans suffer from chronic neuropathic pain which is often refractory to current treatment In search of a solution to this problem of chronic untreatable pain we intend to develop a new analgesic therapy based on modulation of the T type Ca channel T type Ca channels play key roles in pain signaling The Cav family of channels is involved in at least two key stages of pain pathways first at the dorsal root ganglion DRG and again at the thalamic pain relay Both chronic nerve constriction injury and diabetic neuropathy cause upregulation of one of these channels Cav in the DRG neurons of rats Conversely gene knockout antisense knockdown or silencing of the Cav isoform produces good apparent pain relief in both neuropathic and inflammatory pain in rats or mice In short the T type Ca channels appear to be excellent drug targets for treating neuropathic pain In our completed T channel biologic probe discovery project NS Xie through collaboration with the Vanderbilt Screening Chemistry Center we discovered four hit compounds from two different novel chemical scaffolds The best hit ML mitigates chronic pain induced by spared nerve injury streptozotocin induced diabetic neuropathy and reserpine induced chronic pain in rats We have therefore selected ML as the starting compound for chemical optimization in our proposed SBIR Fast Track project for our pain relief drug discovery program We will start with structure activity relationship SAR studies on a focus set of ML derivatives The milestone for advancement from Phase I to Phase II is identification of the top modified leads that meet our selection criteria higher potency and selectivity than ML The milestone for the end of Phase II is the production of a therapeutic candidate generation of sufficient data of in vivo efficacy pilot safety pharmacology and nonGLP toxicology which will help us to make a go no go informed decision for IND enabling studies in a Competing Renewal of SBIR Phase II Once we are ready to conduct IND enabling studies and file an IND application it will be enormously valuable in attracting non government support and industrial partners for clinical development Our ultimate goal is to develop a novel therapeutic with selective and state dependent inhibition of the Cav channel to treat chronic neuropathic pain PUBLIC HEALTH RELEVANCE Millions of Americans suffer from chronic pain especially neuropathic pain which is often not well treated and dramatically reduces their quality of life We propose to develop a novel therapeutic that selectively reduces abnormal chronic pain without interfering with normal pain sensation through normalizing sensory neuronal activity