TREATING SELF-ABUSE IN AUTISM AND MENTAL RETARDATION

长期目标：Serenix制药公司（SP）将开发治疗自闭症、图雷特综合症和智力迟钝患者的冲动、暴力和自残行为的药物。这些药物被称为“宁静剂”，在不干扰正常行为的情况下阻止暴力行为。没有其他产品可用于这些适应症。策略：SP从礼来公司获得一系列拮抗剂，阻断参与攻击的受体亚型。这些拮抗剂（LEAD系列）对人类受体具有高亲和力（<1.0 nM），在胃和血液中稳定，口服有效，并能进入大脑。它们需要改进以优化这些特性。平台分子有四个基本的结构区，可以修改以提高生物利用度。第一阶段的目标是(I)利用组合化学修饰LEAD系列的结构区，生成约200种化合物，（ii）筛选这些化合物的靶受体亲和力，并重点关注Kds < 5 nM的化合物，（iii）测试高亲和力化合物的体外生物活性，以及（iv）测试生物活性化合物对动物攻击模型的体内作用。该研究结果将确定有希望的化合物用于II期口服吸收、稳定性、中枢神经系统渗透、代谢和毒性测试，以及在灵长类动物自残行为模型中的有效性。建议的商业应用：SP将专注于开发有助于控制冲动、暴力和自残行为的药物，用于治疗自闭症、图雷特综合征和智力迟钝。据估计，仅在美国就有50多万患者需要这些药物。这些药物也可用于控制与躁狂症相关的暴力，ADHD儿童亚群的行为障碍和阿尔茨海默病。目前市场上还没有针对这些适应症的其他产品。

Long Term Goals: Serenix Pharmaceuticals (SP) will develop drugs to treat impulsivity, violence, and self-injurious behavior in patients with autism, Tourette's syndrome, and mental retardation. These drugs, termed serenics, stop violent behavior without disrupting normal behaviors. No other products are available for these indications. Strategy: SP acquired a series of antagonists from Eli Lilly and Company that block the receptor subtype involved in aggression. These antagonists (LEAD SERIES) exhibit high affinity for the human receptor (<1.0 nM), are stable in stomach and blood, orally active, and pass into the brain. They require refinement to optimize these characteristics. The platform molecule has four essential structural zones that can be modified to improve bioavailability. Phase I objectives are (i) utilize combinatorial chemistry to modify structural zones on the LEAD SERIES to generate ca. 200 compounds, (ii) screen these for target receptor affinity and focus on those with Kds < 5 nM, (iii) test the high affinity compounds for in vitro biological activity, and (iv) test biologically active compounds for in vivo effects on an animal model of aggression. The findings will identify promising compounds for testing in Phase II for oral absorption, stability, CNS penetration, metabolism, and toxicity as well for efficacy in a primate model of self-injurious behavior. PROPOSED COMMERCIAL APPLICATION: SP will focus on the development of drugs to help in the control impulsivity, violence, and self-injurious behavior for the management of autism, Tourette' s syndrome, and mental retardation. It is estimated that more than 500,000 patients in the United States alone would have a need for these drugs. These drugs may also be used in the control of violence associated with mania, conduct disorder in a sub set of children with ADHD, and Alzheimer' s disease. There are no other products on the market for these indications.