Hit-to-lead optimization for sleeping sickness drug discovery

 描述(申请人提供)：人类非洲锥虫病(HAT)是一种被忽视的热带疾病(NTD)，需要新的口服药物。作为NTD，用于发现新药的资金是有限的。因此，我们一直在应用一种务实的方法，即重新调整人类激酶抑制剂支架的用途，以发现抗锥虫的先导。从FDA批准的药物拉帕替尼开始，我们在系统的药物化学活动中设计和合成了380多个新的类似物。拉帕替尼可以杀死培养的血液锥虫(EC50=1600 NM)，选择性指数(SI)=4(与对人HepG2细胞的活性相比)。着眼于改善SI、毒性分布、新陈代谢、物理化学性质和CNS可用性，我们的新系列包括先进的HITS，在效力(EC50)、SI和水溶解度(AQ)方面远远优于拉帕替尼。SOL.)。它们包括NEU-1060(EC50=6 NM，SI&GT；2333)、NEU-1912(EC50=24 NM，SI&GT；1458)和NEU-1953(EC50=420 NM，SI&GT；100，AQ。索尔=43微米)。通过直接比较neu-1912与拉帕替尼，以下关键进步是显著的(I)EC50提高了67倍；(Ii)SI提高了355倍；(Iii)亲脂配体效率(LLE)提高了400%。Neu-1912，在一项概念验证研究中， 与对照(未治疗)小鼠相比，感染锥虫的小鼠寿命延长。在微调neu-1912的物理化学性质的初步尝试中，我们已经将neu-2091的溶解度提高了48倍，并赋予了neu-1060的中枢神经系统渗透特性。我们现在建议通过引入取代基来将neu-1912化学类型转化为潜在的先导化合物，从而改善相关类似物的物理化学、代谢或CNS可用性。对于发现的新线索，我们将执行行动模式，确定线索的目标，并从基因上验证它们对锥虫增殖的重要性。我们项目的总体目标是在未来五年内提供五种符合HAT主要标准的化合物。这些化合物将作为临床前研究新药处于有利地位。

 DESCRIPTION (provided by applicant): Human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) for which new orally available drugs are needed. As an NTD, funds for discovery of new drugs are limited. Therefore, we have been applying a pragmatic approach of "repurposing" human kinase inhibitor scaffolds for anti-trypanosome lead discovery. Starting with the FDA-approved drug lapatinib, which killed cultured bloodstream trypanosomes (EC50 = 1600 nM) and had a selectivity index (SI) = 4 (compared to activity against human HepG2 cells), we designed and synthesized over 380 new analogs in a systematic medicinal chemistry campaign. With an eye towards improving SI, toxicity profile, metabolism, physicochemical properties, and CNS availability, our new series includes advanced hits, which are vastly superior to lapatinib in potency (EC50), SI, and aqueous solubility (Aq. Sol.). They include NEU-1060 (EC50 = 6 nM, SI > 2333), NEU-1912 (EC50 = 24 nM, SI > 1458), and NEU-1953 (EC50 = 420 nM, SI > 100, Aq. Sol. = 43 µM). By directly comparing NEU-1912 to lapatinib, the following key advances are notable (i) 67-fold EC50 improvement; (ii) over 355-fold SI enhancement; and (iii) a 400% increase in lipophilic ligand efficiency (LLE). NEU-1912, in a proof-of-concept study, prolonged life of trypanosome-infected mice as compared to control (untreated) mice. In initial attempts to fine-tune physicochemical properties of NEU-1912, we have increased solubility 48-fold in NEU-2091, and conferred CNS penetration features with NEU-1060. We propose now to focus our efforts on converting the NEU-1912 chemotype into potential leads, by incorporating substituents that improved physicochemical, metabolic or CNS availability of related analogs. For new leads identified, we will perform mode of action, identify the targets for the leads, and genetically validate their importance for trypanosome proliferation. The overarching goal of our project is to deliver five compounds that meet Lead Criteria for HAT in the next five years. Such compounds will be well-positioned for advancement as preclinical investigational new drugs.