Developing a Novel, Fungicidal Therapeutic to Treat Coccidioidomycosis

 描述（由申请人提供）：球孢子菌病，通常称为山谷热（VF），是一种侵袭性真菌感染，在美国西南部温暖干燥的气候中流行，当病原体的空气传播孢子进入肺部时发生感染。在美国，这种疾病的估计年发病率约为每年150，000例。虽然约60%的球孢子菌病病例无症状，但其余40%的患者表现出症状，包括自限性咽喉痛、发热、咳嗽、疲劳和胸痛，其中一些患者进展为使人衰弱、危及生命的播散性疾病。自限性症状可持续数周或数月，由于工作损失和后续医生预约的成本，导致大量的发病成本。此外，仅在加州，由于球孢子菌病而住院的年经济负担平均约为1.9亿美元，住院患者的相关死亡率为8%。最近，Ampalix Pharmaceuticals已经从Kidai获得了整个有效Gwt 1抑制剂组合的许可。这些化合物中的几种显示出1）与两种C相比具有良好的效价（M100 ≤ 0.13 µg/mL）。immitis和C. posadasii; 2）在小鼠和大鼠模型中超过45%的口服生物利用度; 3）基于体外P450测定，药物-药物相互作用的可能性低; 4）在啮齿动物中的血浆水平下没有可观察到的毒性，这应该允许强的抗真菌活性;以及5）强的体内功效数据。我们计划利用由Risai的化学团队阐明的广泛的结构-活性关系（SAR）来改进我们的“命中”化合物的性质，采用以下具体目标：目标1。创建第一代文库，其中至少有25种来自第一阶段的热门化合物的类似物。目标二。通过采用体外试验评估2a）抗真菌效力; 2b）靶向接合; 2c）细胞毒性; 2d-2 i）体外PK/PD，表征和选择化合物以进行改进。目标3：通过采用体内研究评估a）PK; B）最大耐受剂量; c）真菌负荷的减少; d）VF模型中存活率的改善，表征和选择化合物以进行改进。

 DESCRIPTION (provided by applicant): Coccidioidomycosis, more commonly known as Valley Fever (VF), is an invasive fungal infection that is endemic to the warm, dry climate found in the Southwestern United States, Infection occurs when airborne spores of the pathogen enter the lungs. The estimated annual incidence of this illness in the U.S. is about 150,000 cases per year. Although about 60% of coccidioidomycosis cases are asymptomatic, the remaining 40% of patients manifest symptoms including self-limiting sore throat, fever, cough, fatigue, and chest pain, with some patients progressing to debilitating, life-threatening disseminated disease. The self-limiting symptoms can persist for weeks or months resulting in a substantial morbidity cost due to work lost and the costs of follow-up physician appointments. Moreover, the annual economic burden in California alone from hospitalizations due to coccidioidomycosis is on average about $190 million and the associated mortality rate for those patients hospitalized is 8%. Recently, Amplyx Pharmaceuticals has in-licensed the entire portfolio of potent Gwt1 inhibitors from Eisai. Several of these compounds show 1) good potency (M100 ≤ 0.13 µg/mL) vs. both C. immitis and C. posadasii; 2) over 45% orally bioavailability in mouse and rat models; 3) low potential for drug-drug interactions based on in vitro P450 assays; 4) no observable toxicity at plasma levels in rodents that should permit strong antifungal activity; and 5) strong i vivo efficacy data. We plan to leverage the extensive structure- activity relationships (SAR) elucidated by the chemistry team at Eisai to refine the properties of our "hit" compounds employing the following Specific Aims: Aim 1. Create a first generation library of at least 25 analogues of hit compounds from Phase I. Aim 2. Characterize and select compounds for advancement by employing in vitro assays to assess 2a) antifungal potency; 2b) target engagement; 2c) cytotoxicity; 2d-2i) in vitro PK/PD. Aim 3. Characterize and select compounds for advancement by employing in vivo studies to assess a) PK; b) maximum tolerated dose; c) reduction of fungal burden; d) improved survival in VF models.