Norketamine for Treatment of Pain

描述（由申请人提供）：慢性疼痛是一个重要的医学问题。它的治疗，特别是慢性神经性疼痛，仍然是一个未满足治疗需求的领域。作为n -甲基- d -天冬氨酸（NMDA）受体拮抗剂的化合物是治疗神经性疼痛的一组重要的潜在药物。这类药物也被证明可以增强吗啡的镇痛作用，抑制对这种阿片类药物的耐受性发展。尽管氯胺酮是一种很有前景的镇痛药，但其唯一可用的NMDA受体拮抗剂氯胺酮的临床用途受到限制，因为它具有拟精神、镇静和运动副作用。这促使人们努力寻找其他NMDA受体拮抗剂，这些拮抗剂保留了镇痛特性，但具有更可接受的副作用。该项目的第一阶段STTR资助表明，新型NMDA受体拮抗剂诺氯胺酮（NK）及其对构象[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，我们已经确定了诺氯胺酮，特别是S(-)- nk，作为一种治疗神经性疼痛的新型药物具有发展潜力的可行性。STTR II期资助的最终目标是开发一种副作用更少、更可耐受的NMDA受体拮抗剂，用于治疗慢性疼痛。II期STTR提案的具体目标是：1)在已建立的大鼠疼痛和行为模型中，与R(+)- NK相比，进一步表征S(-j-NK的药理学特征；2)进行S(-)- nk的非cgmp批量合成用于临床前研究；3)评估口服生物利用度，评估代谢谱，确定S(-)- nk在大鼠体内的最佳口服剂量；4)提供原料药的批量生产工艺，制定S(-)- nk口服胶囊剂型，获得cGMP S(-)- nk和cGMP安慰剂用于I期临床试验；5)评估S(-)- nk的毒理学特性，包括神经毒性；6)开展I期临床试验，评估S(-) NK的安全性。总之，I期STTR研究结果已经确定了S(-)- nk作为神经性疼痛药物进一步开发的可行性。II期STTR提案将建立在I期STTR发现的基础上，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，总体目标是进入人体I期临床试验。开发一种临床有用的慢性神经性疼痛药物，将在治疗癌症、aids、神经病变、糖尿病性神经病变、复杂区域疼痛综合征和神经根病等疼痛方面具有潜在的广泛应用前景。

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.