Phosphodiesterase Type IV (PDE4) Isoform Selective Allosteric Modulators For Psyc

描述(由申请人提供)：SBIR提案的主要目标是了解中枢神经系统中磷酸二酯酶4(PDE4)变构调节的药理学，因为它与精神疾病有关。我们最近发现了PDE4D的异构体选择性变构调节剂，它与N-末端调节域上的一个高亲和力位点结合，称为上游保守区2(UCR2)。变构作用机制阻止了化合物完全抑制cAMP水解，从而降低了靶标毒性。与罗利普兰等早期化合物相比，PDE4D调节剂的耐受性有了很大提高。罗利普兰此前在人类第二阶段临床试验中被证明具有抗抑郁活性，但由于呕吐而耐受性较差。PDE4的三种异构体在脑中表达(PDE4A、B和D)。以前还不可能开发具有异构体选择性的PDE4抑制剂，因为早期的努力针对的是在PDE4亚型中高度保守的催化位点；因此，关于PDE4异构体选择性化合物的药理知之甚少。我们的近期目标是探索我们的研究新药DG-071在精神疾病，特别是抑郁症的动物模型中可能的临床益处。拟议的研究将确定开发用于治疗抑郁症的DG-071的可行性。SBIR建议的第二个具体目标是使用结构指导来设计分布在大脑中的PDE4B选择性变构调节剂。我们将探索PDE4B中枢神经系统的药理学，特别是在精神分裂症的模型中。结构和药物化学研究将确定在第二阶段SBIR中开发PDE4B选择性变构调节剂治疗精神疾病的可行性。 公共卫生相关性：严重形式的抑郁症影响着2-5%的美国人口，情绪障碍影响着世界7%的人口，并跻身于前十大致残原因之列。我们正在寻求一种基于对磷酸二酯酶4D的变构调节来治疗抑郁症的新方法。

DESCRIPTION (provided by applicant): The broad goal of the SBIR proposal is to understand the pharmacology of phosphodiesterase 4 (PDE4) allosteric modulation in the CNS as it relates to psychiatric disorders. We recently described the discovery of isoform-selective, allosteric modulators of PDE4D that bind to a high affinity site on an N-terminal regulatory domain known as Upstream Conserved Region 2 (UCR2). The allosteric mechanism of action prevents the compounds from completely inhibiting cAMP hydrolysis, thereby reducing target-based toxicity. PDE4D modulators have greatly improved tolerability than earlier compounds such as rolipram. Rolipram previously was shown to have anti-depressant activity in human Phase II clinical trials but was poorly tolerated due to emesis. Three isoforms of PDE4 are expressed in brain (PDE4A, B & D). It previously has not been possible to develop isoform-selective PDE4 inhibitors, since earlier efforts have targeted the catalytic site, which is highly conserved among the PDE4 subtypes; thus, little is known regarding the pharmacology of PDE4 isoform selective compounds. Our immediate goal is to explore the possible clinical benefit of our investigational new drug, DG-071 in animal models of psychiatric disease, particularly depression. The proposed studies will determine the feasibility of developing DG-071 for the treatment of depression. The second specific aim of the SBIR proposal is to use structural guidance to design PDE4B selective allosteric modulators that distribute to brain. We will explore PDE4B CNS pharmacology, particularly in models of schizophrenia. The structural and medicinal chemistry studies will determine the feasibility in a Phase II SBIR of developing PDE4B selective allosteric modulators for psychiatric disorders. PUBLIC HEALTH RELEVANCE: Severe forms of depression affect 2-5% of the US population, and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. We are seeking to develop a new treatment for depression based on allosteric modulation of phosphodiesterase 4D.