A Safe Analgesic Drug with Addiction Treatment Potential

描述（由申请人提供）：本SBIR拨款旨在将一种有前途和需要的药物NIH 10497（D-1）商业化。它是一种新颖的口服活性阿片类药物，具有独特的手性n取代基，具有前所未有的活性。它有望成为一种安全有效的镇痛药，也有望成为一种治疗成瘾的药物，但不是维持成瘾，而是有可能治愈成瘾。NIH 10497已经被NIDA资助的研究表明，在kappa， mu和delta阿片受体上具有不寻常的激动剂活性平衡。特别是，该药物在依赖动物中被发现可以替代吗啡，而在非依赖动物中则不会产生身体依赖。这表明了一种新的活动概况。NIH 10497最初于1980年发现，但从未上市。NIH 10497的发明者创立了一家小型企业，凤凰制药公司，目的是将这种药物商业化。我们的第一个目标是为新用途创建新的专利（原始专利已经过期），并在SBIR的支持下，为立体选择性和可扩展的大规模合成的关键新方法创建新的专利。这将需要发现使用手性还原剂的改进的还原性胺化步骤。NIH 10497也缺乏足够的体内评估，因此在这笔拨款下，与Lou Harris博士达成的联合协议将资助VCU大鼠的吗啡替代研究（MSS）。

DESCRIPTION (provided by applicant): This SBIR grant is sought for the purpose of commercializing a promising and needed drug NIH 10497(D-1). It is a novel, orally active opioid with a unique chiral N-substituent that confers an unprecedented activity profile. It has promise as a safe potent analgesic and as a treatment for addiction, not with maintenance, but with potential for cure. NIH 10497 has already been shown by NIDA funded studies to possess an unusual balance of agonist activities at the kappa, mu, and delta opioid receptors. In particular, the drug was discovered to substitute for Morphine in dependent animals, while causing no physical dependence in non-dependent animals. This suggests a novel profile of activities. NIH 10497 was originally discovered in 1980 but was never marketed. The inventor of NIH 10497 founded a small business, Phoenix PharmaLabs, for the purpose of commercializing this drug. Our first goal is to create fresh Patents (the original Patents have expired) for a new Use and, with SBIR support, for a critical new Method of large-scale synthesis that is stereoselective and scalable. This will require the discovery of an improved reductive amination step using a chiral reducing agent. NIH 10497 also lacks sufficient in vivo evaluation, so under this grant, a consortium agreement with Dr. Lou Harris will fund a Morphine Substitution Study (MSS) in the rat at VCU. The PI and two of the consultants, Dr. Toll and Dr. Lukeman have traveled to China three times to meet with Ms. Peng Yan and interested investors. Investors are attracted to NIH 10497 for a number of reasons. Toxicology and Clinic trials are much less expensive in China and there is strong need for a treatment of addiction in that country. The PI and Dr. DeGraw will develop new synthetic methods for NIH 10497 to achieve a Method Patent that is crucial to attract the Investor. Dr. Harris will supervise the MS study in rats, and Dr. Lukeman will assist in the pharmacologic assessment of the results and determine the valuation of NIH 10497 in preparation for commercialization.