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

18-甲氧基冠状病毒盐酸盐（18-

• 批准号: 8720743
• 负责人: Scott M. Freeman
• 金额: $ 62.02万
• 依托单位: SAVANT HWP, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720743
• 关键词: Action Potentials; Affect; Alcohols; Amygdaloid structure; Animal Model; Animals; Applications Grants; Attenuated; Behavior; Bone Marrow; Canis familiaris; Cannabis; Cardiac; Cardiovascular system; Cholinergic Receptors; Chromosome abnormality; Clinic; Clinical; Clinical Research; Cocaine; Cocaine Abuse; Contracts; Cues; Data; Development; Disease; Dose; Future; Grant; Hepatocyte; Human; Hydrochloride Salt; In Vitro; Individual; Lead; Lethal Dose 50; Libraries; Liver Microsomes; Manufacturer Name; Manuscripts; Methamphetamine; Microsomes; Modeling; Morphine; Mus; Mutation; Neurons; Neuropharmacology; Neurosciences; Nicotine; Nicotinic Receptors; No-Observed-Adverse-Effect Level; Oryctolagus cuniculus; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Production; Research; Safety; Self Administration; Societies; Structure of purkinje fibers; Substance-Related Disorders; Time; Toxicology; United States Food and Drug Administration; base; cocaine use; coronardine; cost; dosage; economic cost; improved; in vivo; innovation; micronucleus; novel; receptor; research study; respiratory; safety study; scale up; stability testing; treatment duration

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.

描述（由适用提供）：需要新药物治疗与物质有关的疾病（SRDS）的需求至关重要，因为仅SRDS仅在美国就会不利影响数千万人。目前，食品药品监督管理局批准用于治疗SRD的药物是最佳的。此外，没有批准可卡因，甲基苯丙胺或大麻使用障碍的药物。基于神经药理和神经科学的最新进展的新药物的开发和批准有可能改善数百万遭受SRD苦难的生活。 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基底外侧杏仁核，以治疗SRD。这项赠款提案的目的是开发和扩大GMP的生产18-MC，并在可卡因使用障碍的个体中对IND和人类（FTIH）研究的支持和体内毒理学研究完成。当前的数据显然支持18-MC治疗SRD的持续开发。未满足的药物治疗可卡因使用障碍的需求强调了我们的助学后策略将18-MC转移到诊所和FTIH研究中的重要性，而在这种疾病的患者中，提示诱导的药物寻求药物尤其具有挑战性，例如可卡因的使用尤其具有挑战性。在研究条件下，从批量少于30克的18-MC生产中的当前数据将用于使GMP合同制造商能够开发和扩展GMP制造，最高1.0千克批次的18-MC活性药物累列（API）（API）用于未来的临床研究和ICH稳定性研究，以实现药物的开发和制造。来自Savant研究的数据将用于使用GMP 18-MC为辅助GLP研究提供信息。 GLP的体外研究将包括细菌反向突变，人肝微粒体中人类外周血淋巴细胞中的染色体像差，p450以及兔紫kinje纤维中的心脏动作潜在的持续时间以及体内小鼠微核，所有这些都将在大规模的动物氧化质学研究中前进。辅助GLP鼠毒理学研究将包括：7天重复剂量研究；一项为期28天的重复剂量研究，评估低剂量，中等和高剂量，以识别NOAEL和CNS效应；呼吸安全研究；和可卡因相互作用研究。辅助GLP狗毒理学研究将包括：剂量发现研究； 7天和28天的研究低剂量和高剂量以识别Noael；可卡因相互作用研究；以及一项剂量心血管效应研究。