Positive Allosteric Modulators (PAMS) of Strychnine-Sensitive Glycine Receptors - A New Concept in Treating Chronic Pain

问题/背景：我们的项目解决了长期迫切的、未得到满足的慢性疼痛的医疗需求。在欧洲和美国，这种令人衰弱的疾病影响着大约20%的成年人，即仅在英国就有800多万成人患者，摧毁了个人生活，造成了巨大的经济损失，主要是损失的工作日。一个关键的问题是，目前可用的对症药物只对大约40%的慢性疼痛患者有效，即使是这些患者也在努力保持足够的疼痛缓解和他们应对药物引起的实质性不良反应之间的平衡。这造成了止痛不足和无法承受的副作用的恶性循环，最终导致停止治疗。尽管存在这些问题，但预计到2017年，仅神经性疼痛市场的增长就将超过63亿美元。概念：对于理解慢性疼痛的病理生理学，有证据表明脊髓内抑制性神经元传递的丧失起着关键作用。这种抑制神经活动的能力下降，与钢琴内部有缺陷的阻尼器相当，导致了中枢神经系统的功能性平衡失调状态，称为中枢疼痛敏感化。这种丢失涉及一种特殊类型的细胞膜跨膜蛋白通道，由不同的信使分子操作，主要是甘氨酸。因此，甘氨酸能神经传递的增强应该可以弥补这种损失。我们的建议/解决方案-一种首创的因果治疗：因此，我们建议开发一类新的化合物，确实能够有效和选择性地增强脊髓水平的甘氨酸能神经传递，从而达到预期的效果，同时避免不想要的和危险的副作用，例如深度镇静/意识丧失。到这个项目结束时，我们应该准备好开发一种药物，这种药物将在有限的时间内口服，以重新设置患者中枢神经系统的适当平衡状态。我们的最终目标是让慢性疼痛患者重新获得显著提高的生活质量。迄今所取得的成就：我们已经成功地发现/合成了一类新的化合物，这些化合物对士的宁敏感的甘氨酸受体具有选择性增强作用，而士的宁敏感的甘氨酸受体不介导镇静作用。我们相信，这一功能使我们的开发计划具有很强的竞争力、可行性和重要性，并通过申请合成物质专利来保护知识产权。此外，我们还在神经病理性疼痛的大鼠模型中获得了一种关键化合物的概念验证。工作计划：该项目目前处于快速发展阶段，即我们已经知道我们的概念是可行的，但我们需要进一步改进我们化合物的化学特征，为我们的最终目标做准备，即产生安全/有效且可以口服的药物，例如每天3次。我们计划在两年内实现这种优化的领先地位。影响：鉴于全球有大量患者的生活受到慢性疼痛的破坏，当前的治疗选择明显不足，以及数百万工作时间损失对经济造成的巨大损失，可以肯定地说，我们首创的因果治疗方案有可能对个人和社会产生巨大的有益影响。我们的解决方案有潜力成为一个平台-技术：我们相信，我们的建议可以提供一个平台技术，解决进一步的医疗状况，例如阿片类药物戒断、酒精中毒和焦虑。计划的进入市场/退出战略：Grunenthal和B.Braun两家制药公司已经确认，如果成功完成这一计划，他们希望与我们的集团以及彼此合作。

The Problem/Background: Our project addresses the longstanding urgent, unmet medical need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, i.e. more than 8 million adult patients in the UK alone, wrecking individual lives and causing huge economical damage, predominantly in terms of lost working days. One key issue is the fact that the symptomatic medication currently available is effective only in about 40% of chronic pain sufferers and even these patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive drug-induced adverse effects. This creates a vicious cycle of insufficient analgesia and unbearable side effects ultimately leading to discontinuation of treatment. Despite these problems growth in the neuropathic pain market alone is forecasted to rise to over $6.3 billion by 2017. The Concept:As regards understanding the pathophysiology of chronic pain there is evidence that loss of inhibitory neuronal transmission within the spinal cord plays a key role. This reduced capacity to inhibit nerve activity, comparable to defective dampers inside a piano, contributes to a functional dysequilibrium state of the central nervous system referred to as central pain sensitisation. The loss involves a particular type of cell membrane-spanning protein channels operated by distinct messenger molecules, mainly glycine. Thus, enhancement of glycinergic neurotransmission should compensate for this loss. Our Proposal/Solution - A First-In-Kind Causal Treatment: Consequently, we propose to develop a novel class of compounds which do enhance glycinergic neurotransmission effectively and selectively at the spinal cord level, thereby achieving the intended effect while avoiding unwanted and dangerous side effects, e.g. deep sedation/loss of consciousness. By the end of this project we should to be ready for development into a drug that will be taken orally for a limited period of time in order to reset the proper equilibrium state of the patient's central nervous system. Our ultimate aim is allowing chronic pain patients to regain a dramatically improved quality of life.What has been achieved so far: We have successfully progressed to the discovery/synthesis of a novel class of compounds with selective enhancing effects at strychnine-sensitive glycine receptors, which do not mediate sedative effects. We are confident that this feature makes our development program highly competitive, viable and significant and have protected the Intellectual Property by filing a composition of matter patent. Moreover, we have obtained proof-of-concept for one key compound in a rat model of neuropathic pain. Work Plan: The project is currently in the hit-to-lead stage development stage, i.e., we do already know that our concept works but we need to further improve chemistry features of our compounds in preparation for our ultimate aim, i.e. generating drugs which are safe/effective and can be taken orally, e.g. 3 times/day. We plan to achieve such optimised leads within two years. Impact:In view of the huge numbers of patients worldwide whose lives are wrecked by chronic pain, the fact that current treatment options are clearly insufficient and the dramatic toll on economies caused by millions of lost working hours, it is safe to say that our first-in-kind causal treatment option has the potential to have a dramatic beneficial impact on individuals and societies.Our Solution Has Potential To Be A Platform-Technology:We are confident, that our proposal can provide a platform technology addressing further medical conditions, e.g., opioid-withdrawal, alcoholism and anxiety. Planned Route-to-Market/Exit Strategy: Two pharmaceutical companies, Grunenthal and B.Braun have confirmed their desire to collaborate with our group, and each other, in the event of a successful completion of this programme.