Rational Development of Thyroid Receptor Antagonists

描述(由申请人提供)：Molsoft建议开发针对甲状腺激素受体(TR)的拮抗剂铅分子，IC50在低纳米范围内，并具有良好的生物利用度、特异性和毒性特征。概念验证在第一阶段实现，Molsoft的虚拟配体筛选技术允许发现14个小分子受体拮抗剂表现出极端的结构多样性，IC50从4微米到30微米不等。此外，在第一阶段设计的测试用例领先优化方案，基于生成易于有机并行合成的分子的聚焦虚拟文库，导致在第二阶段快速识别IC50在纳摩尔范围内的第二代命中，我们建议对第一阶段确定的命中中的最多3个进行全面优化循环。我们期待Molsoft的计算机建模专家、有机并行合成专家和纽约大学的TR生物学专家的协同努力，在第一阶段得到验证，将在第二阶段产生低纳摩尔命中率。此外，还将使用一系列计算工具、体外鉴定和初步动物研究来评估活性分子的生物利用度、特异性和毒性，并识别新的化学实体，这些新化学实体具有更大的可能性，可导致对制药业具有吸引力的成功临床候选药物。

DESCRIPTION (provided by applicant): Molsoft proposes to develop antagonist lead molecules against the thyroid hormone receptor (TR) with IC50s in the low nanoM range and favorable bioavailability, specificity, and toxicity profiles. Proof of concept was achieved in Phase I Molsoft's virtual ligand screening technology allowed the discovery of 14 small molecule TR antagonists displaying extreme structural diversity, with IC50s ranging from 4 to 30 microM Additionally, the test-case lead optimization scheme designed in Phase I, based on generating focused virtual libraries of molecules easily amenable to organic parallel synthesis, resulted in rapid identification of 2nd generation hits with IC50 in the nanomolar range In Phase II, we propose to conduct full-scale optimization cycles of up to 3 of the hits identified in Phase I We expect that the synergistic efforts of computer modeling specialists at Molsoft, organic parallel synthesis, and TR biology experts at New York University, validated in Phase I, will produce low nanomolar hits in Phase II Additionally, a series of computational tools, in vitro characterization, and preliminary animal studies will be used to evaluate the bioavailability, specificity, and toxicity of active molecules and identify new chemical entities with enhanced likelihood of leading to successful clinical candidates attractive to the pharmaceutical industry.