Discovery of T-type Calcium Channel Antagonists from Multicomponent Reactions and Their Application in Paclitaxel-induced Peripheral Neuropathy

Summary Abstract Chemotherapy induced peripheral neuropathyCIPNis detected inof cancer patients during all phases of cancerSensory symptoms in the hands and or feettypically in astocking glovepatternare commonand manifested as painnumbnessand or tinglingCIPN can result in chemotherapy dose reduction or discontinuationand can also have long term effects on the quality of lifeThe course of CIPN can be unpredictablewhile symptoms may resolve after chemotherapy is discontinuedthey can also continue for yearsSince its introduction in thesthe antimicrotubule PaclitaxelTaxolhas been used as an effective anticancer agent against lungbreastovarianleukopenia and liver cancerButPaclitaxel induced peripheral neuropathy is the major dose limiting side effect of paclitaxelTaxaneslike Paclitaxelmay cause structural damage to peripheral nervesresulting in aberrant somatosensory processing in the peripheral and or central nervous systemDorsal root gangliaDRGsensory neurons as well as neuronal cells in the spinal cord are key sites in which chemotherapy induced neurotoxicity occursPathogenesis is complex but includes dysregulation of ion channelsFor examplePaclitaxel increases expression of low voltage activated T typeCavCachannels in rat DRG neuronsthese neurons are responsible for conveying noxious sensory stimulisuggesting these channels are important mediators of specific sensory abnormalities associated with CIPNT type Cachannels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic painThough Cavhas been targeted clinically with small molecule antagonistsno drugs targeting these channels have advanced to phase II human clinical trialsThis proposal aims to explore multicomponent reaction productsdeveloped in the laboratory of the PIDrJun Wangfor the rapid identification of potent and selective T type Cachannel antagonistsFor this workwe have partnered with DrRajesh KhannaPI and Chief Scientific OfficerRegulonixLLCfor characterizing select compounds and their analogs in in vitro and in vivo efficacy assays as well PK optimizationThe work proposed here is the first step in developing non opioid pain treatments for CIPNWe anticipate success against paclitaxel induced chronic pain will translate into other chronic pain types as wellbut CIPN provides focus for early stage proof of conceptRegulonixandapos s specific aims areDesign and synthesis of UAWJanalogs and elucidation of channel specificity and biophysical properties of select UAWJs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cellsProfile the in vitro cellular cytotoxicity and pharmacokinetic properties of UAWJanalogsCharacterize the best two UAWJsfrom Aimfor preclinical studies using a neuropathic pain modelpaclitaxelto provide information about efficacyAt the conclusion of our studywe expect to have a validated UAWJ analog and several worthy backup compounds Narrative Chemotherapy induced peripheral neuropathyCIPNis detected inof cancer patients during all phases of cancerfor which there is no effective treatment at the momentTo address this unmet medical needwe propose to develop potent and selective T type Cachannel antagonists as novel pain medicines for the management of CIPNSuccessful execution of this proposal is expected to provide pain relief to cancer patientsincrease their compliance of chemotherapyand improve their well being