Phosphodiesterase 4 Subtype Selective Modulators for Psychiatric Disease

描述（由申请人提供）：SBIR提案的总体目标是了解与精神疾病相关的中枢神经系统磷酸二酯酶4 （PDE4）变张调节的药理学。我们最近描述了PDE4D的同型选择性变构调节剂的发现，该调节剂结合到n端调节域的高亲和力位点，称为上游保守区2 （UCR2）。变构作用机制防止化合物完全抑制cAMP水解，从而降低靶向毒性。PDE4D调节剂的耐受性大大提高，比早期的化合物，如罗利普兰。罗利普兰先前在人类II期临床试验中显示出抗抑郁活性，但由于呕吐而耐受性差。PDE4的三种同工异构体在脑内表达（PDE4A， B和D）。以前不可能开发出具有异构体选择性的PDE4抑制剂，因为早期的研究针对的是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学知之甚少。我们的近期目标是探索我们正在研究的新药DG-071在精神疾病，特别是抑郁症动物模型中的临床疗效。拟议的研究将确定开发DG-071治疗抑郁症的可行性。SBIR提案的第二个具体目标是使用结构指导来设计分布到大脑的PDE4B选择性变构调节剂。我们将探讨PDE4B中枢神经系统药理学，特别是在精神分裂症模型中。结构和药物化学研究将确定开发PDE4B选择性变构调节剂用于精神疾病的II期SBIR的可行性。

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.