Rational Development of Thyroid Receptor Antagonists

描述（由申请人提供）：Molsoft拟开发针对甲状腺激素受体（TR）的拮抗剂先导分子，其IC 50在低nanoM范围内，生物利用度、特异性和毒性特征良好。 Molsoft的虚拟配体筛选技术允许发现14种显示出极端结构多样性的小分子TR拮抗剂，IC 50范围为4至30 μ M。此外，在第一阶段设计的测试用例先导优化方案，基于生成易于进行有机平行合成的分子的集中虚拟文库，在第二阶段，我们建议对第一阶段鉴定的多达3个命中进行全面优化循环。我们期望Molsoft的计算机建模专家、有机平行合成和纽约大学的TR生物学专家的协同努力，此外，将使用一系列计算工具、体外表征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，并鉴定新的化学实体，其具有导致对制药工业有吸引力的成功临床候选物的增强的可能性。

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.