Norketamine for Treatment of Pain

描述（由申请人提供）：慢性疼痛是一个重大的医学问题。其治疗，特别是慢性神经性疼痛，仍然是一个未满足的治疗需求领域。用于治疗神经性疼痛的一组重要的潜在药物是作为N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的化合物。这类药物也被证明可以增强吗啡的镇痛作用，并抑制对这种阿片类药物的耐受性发展。尽管氯胺酮作为镇痛药前景广阔，但由于其具有拟精神病、镇静和运动副作用，唯一可用的NMDA受体拮抗剂氯胺酮的临床用途受到限制。这促使人们致力于鉴定保留镇痛性质但具有更可接受的副作用特征的其他NMDA受体拮抗剂。该项目的I期STTR资助已证明，新型NMDA受体拮抗剂去甲氯胺酮（NK）及其对映体[R（+）和S（-）-NK]在啮齿动物神经性疼痛模型中具有镇痛特性。大多数副作用与R（+）-对映体有关。因此，我们已经建立了去甲氯胺酮，特别是S（-）-NK，作为一种新的治疗神经性疼痛的药物开发的潜力的可行性。拟议的第II阶段STTR资助的最终目标是开发一种用于治疗慢性疼痛的NMDA受体拮抗剂，其副作用更少，更容易耐受。II期STTR提案的具体目标是：1）进一步表征S的药理学特征（-j-NK，与R（+）- NK相比，在建立的大鼠疼痛和行为模型中; 2）进行S（-）-NK的非cGMP批量合成用于临床前研究; 3）评价口服生物利用度，评估代谢特征，并确定S（-）-NK在大鼠中的最佳口服剂量; 4）提供该API的批量生产工艺，配制S（-）-NK的口服胶囊剂，获得用于I期临床试验的cGMP S（-）-NK和cGMP安慰剂; 5）评价S（-）-NK的毒理学性质，包括神经毒性; 6）进行I期临床试验，评估S（-）NK的安全性。总之，I期STTR研究结果已经确立了S（-）-NK是进一步开发作为神经性疼痛药物的可行候选物的可行性。II期STTR提案将建立在I期STTR结果的基础上，进一步表征S（-）-NK的药理学和毒理学，以获得研究性新药申请，总体目标是进行人体I期临床试验。临床上用于慢性神经性疼痛的药物的开发将具有潜在的广泛应用，用于治疗疼痛，包括癌症、AID、神经病、糖尿病性神经病、复杂性区域疼痛综合征和神经根病。

DESCRIPTION (provided by applicant): Chronic pain is a significant medical problem. Its treatment, in particular chronic neuropathic pain, remains an area of unmet therapeutic need. An important potential group of drugs for the treatment of neuropathic pain are compounds which act as antagonists at the N-methyl-D-aspartate (NMDA) receptor. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit tolerance development to this opioid. Despite their great promise as analgesics, the clinical usefulness of the only available NMDA receptor antagonist, ketamine, has been limited due to its psychotomimetic, sedative and motor side effects. This has prompted an effort towards identifying other NMDA receptor antagonists which retain analgesic properties but with a more acceptable side effect profile. Phase I STTR funding for this project has demonstrated that the novel NMDA receptor antagonist, norketamine (NK) and its enantomers [R(+) and S(-)-NK] have analgesic properties in a rodent model of neuropathic pain. The majority of side effects are with the R(+)-enantiomer. Thus, we have established the feasibility that norketamine, specifically S(-)-NK, has the potential for development as a novel agent for the treatment of neuropathic pain. The ultimate objective in the proposed Phase II STTR funding is to develop an NMDA receptor antagonist with fewer and more tolerable side effects for the treatment of chronic pain. The specific aims of the Phase II STTR proposal are to: 1) further characterize the pharmacologic profile of S(-j-NK, in comparison to R(+)- NK, in established rat models of pain and behavior; 2) perform non-cGMP bulk synthesis of S(-)-NK for preclinical studies; 3) evaluate the oral bioavailability, assess the metabolic profile, and determine the optimal oral dose of S(-)-NK in the rat; 4) provide a bulk manufacturing process for the API, formulate an oral capsule dosage form of S(-)-NK and obtain cGMP S(-)-NK and cGMP placebo for use in the Phase I clinical trial; 5) evaluate toxicological properties of S(-)-NK including neurotoxicity; 6) conduct a Phase I clinical trial to assess the safety of S(-) NK. In summary, Phase I STTR findings have established the feasibility that S(- )-NK is a viable candidate for further development as a drug for neuropathic pain. The Phase II STTR proposal will build upon Phase I STTR findings to further characterize the pharmacology and toxicology of S(-)-NK, to obtain an Investigational New Drug application, with the overall goal of proceeding to a Phase I clinical trial in humans. The development of a clinically useful drug for chronic neuropathic pain will have potential broad application for the treatment of pain including cancer, AID'S, neuropathy, diabetic neuropathy, complex regional pain syndrome and radiculopathy.