IND-enabling Studies and GMP Scale-up of 18-Methoxycoronaridine hydrochloride(18-

描述（由申请人提供）：需要新的药物来治疗物质相关疾病（SRD）是至关重要的，因为SRD仅在美国就对数千万人产生不利影响。目前，没有食品和药物管理局批准的用于治疗SRD的药物是最佳的。此外，没有批准用于可卡因、甲基苯丙胺或大麻使用障碍的药物。基于神经药理学和神经科学最新进展的新药开发和批准有可能改善数百万SRD患者的生活。 Savant HWP，Inc.正在开发一种新的口服活性药物，18-甲氧基可乐定盐酸盐（18-MC），一种<$3 <$4烟碱胆碱能受体拮抗剂，通过阻断缰-脚间通路和基底外侧杏仁核中的<$3 <$4烟碱受体间接调节多巴胺能中脑边缘通路，以治疗SRD。该拨款提案的目的是开发和扩大18-MC的GMP生产，并完成IND使能的体外和体内毒理学研究，以支持在可卡因使用障碍患者中进行的IND和首次人体（FTIH）研究。 目前的数据明确支持正在进行的18-MC治疗SRD的开发。未满足的药物治疗可卡因使用障碍的需求强调了我们的补助后战略的重要性，即将18-MC转移到临床和FTIH研究中，用于那些线索诱导的药物寻求特别具有挑战性的疾病个体，如可卡因使用。 在研究条件下生产小于30 g批次的18-MC的当前数据将用于使GMP合同生产商能够开发和扩大高达1.0 Kg批次的18-MC活性药物成分（API）的GMP生产，用于开发和生产未来临床研究用制剂，ICH稳定性试验和IND使能性体外和体内GLP研究。 Savant的研究数据将用于为使用GMP 18-MC的IND使能GLP研究提供信息。GLP体外研究将包括细菌回复突变、人外周血淋巴细胞中的染色体畸变、使用人肝微粒体的p450和兔浦肯野纤维中的心脏动作电位持续时间以及体内小鼠微核，所有这些研究都将在更大规模的动物毒理学研究之前进行。IND使能GLP小鼠毒理学研究将包括：一项7天重复给药研究;一项28天重复给药研究，评价低、中和高剂量以确定NOAEL和CNS效应;一项呼吸安全性研究;和一项可卡因相互作用研究。IND使能GLP犬毒理学研究将包括：剂量探索研究;低、中和高剂量的7天和28天研究，以确定NOAEL;可卡因相互作用研究;以及单次给药心血管效应研究。

DESCRIPTION (provided by applicant): The need for new medications to treat Substance-Related Disorders (SRDs) is critical since SRDs adversely affect tens of millions of people in the U.S. alone. Currently, no medication approved by the Food and Drug Administration for the treatment of SRDs is optimal. Also, there are no medications approved for cocaine, methamphetamine or cannabis use disorders. The development and approval of new medications based upon recent advances in neuropharmacology and neuroscience has the potential to improve the lives of millions suffering with SRDs. Savant HWP, Inc. is developing a novel, orally active medication, 18-methoxycoronaridine hydrochloride (18-MC), an ¿3¿4nicotinic cholinergic receptor antagonist that indirectly modulates the dopaminergic mesolimbic pathway via blockade of ¿3¿4nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala, to treat SRDs. The purpose of this grant proposal is to develop and scale-up GMP production of 18-MC and to complete IND-enabling in vitro and in vivo toxicology studies in support of an IND and First Time In Human (FTIH) studies in individuals with cocaine use disorders. Current data clearly support the ongoing development of 18-MC for the treatment of SRDs. The unmet need for medications to treat cocaine use disorders underscores the importance of our post-grant strategy to move 18-MC into the clinic and FTIH studies in individuals with disorders where cue-induced drug seeking is particularly challenging, such as cocaine use. Current data from the production of 18-MC in batches of less than 30g under research conditions will be used to enable a GMP contract manufacturer to develop and scale-up GMP manufacturing of up to 1.0 Kg batches of 18-MC active pharmaceutical ingredient (API) for use in the development and manufacture of drug product for future clinical studies, ICH stability testing and IND-enabling in vitro and in vivo GLP studies. Data from Savant's research studies will be used to inform IND-enabling GLP studies using GMP 18-MC. GLP in vitro studies will include bacterial reverse mutation, chromosome aberration in human peripheral blood lymphocytes, p450 using human liver microsomes and cardiac action potential duration in rabbit Purkinje fibers and in vivo mouse micronucleus, all of which will precede larger scale animal toxicology studies. IND-enabling GLP murine toxicology studies will include: a 7-day repeat dose study; a 28-day repeat dose study evaluating low, intermediate and high doses to identify the NOAEL and CNS effects; a respiratory safety study; and a cocaine interaction study. IND-enabling GLP dog toxicology studies will include: a dose finding study; 7- and 28-day studies with low, intermediate and high doses to identify the NOAEL; a cocaine interaction study; and a single dose cardiovascular effects study.