先导化合物(Leads)的发现
先导化合物的发现是把从筛选中发现的“苗头化合物(hits)”变成可以进一步优化的“先导化合物”的过程。先导化合物可能是筛选出的一个苗头化合物或者一系列的同系物,也可能是来源于文献的化合物。但是对于高通量筛选,可能会产生离散的、多个系列的苗头化合物,这就需要选择其中一个系列继续研究,这个过程被称作“Hit to Lead”。
“Hit to Lead”过程应该注意:
- 紧密结合特定的生物活性和ADME性质
- 平行的生物学评价和“可发展性”评估至关重要
- 密集的数据矩阵
- 高自动化程度,高水平的计算分析
- 周期长短是成功的关键,需要整合体外ADME分析和计算工具
- 计算工具可以发挥重要作用
-
若想外包成功,需要CRO获取所有的化学/生物/化合物/ADME数据
一个好的先导化合物需要满足:
- 从高通量筛选得到足够理想的,多个离散系列的化合物
- 用新鲜的、纯度高的样本确证生物活性和化合物结构
- 体外活性<3μM,合适的功能活性
- 可逆性(Reversibility)
- 可行的选择性实验
- 单个化合物需要合成同系列的小化合物库确证其活性
- 需要5-10个化合物来确证选择的多样性
- 不含不需要的功能性基团或化学反应基团
- 不含毒效团
- 可修饰的化学位点
- 可追踪的物理性质
- 分子量、溶解度、极性
- 对代表性同系物可分析的ADME性质
- 尤其关注合适的口服吸收性质,静脉注射的溶解性和中枢神经系统的渗透性
- ADME问题都是易处理的
*特别注意:生物活性通常是最容易优化的性质。
先导化合物的优化
先导化合物的优化是选择一个先导化合物对其进行临床前评估,将其转化为候选药物的过程:
- 大部分时间都用来解决ADME/T问题
- 分开研究药代动力学和药效学作用持续时间可收获意想不到的益处
- 修饰先导化合物时,密切关注其物理化学性质的变化
- 对于没有选择性的化合物,多多考虑脱靶效应/毒性
- 密切关注临床前研究要求
- 获取经验的最佳途径是从实际工作中以及阅读药物研发的案例
先导化合物的发现是把从筛选中发现的“苗头化合物(hits)”变成可以进一步优化的“先导化合物”的过程。先导化合物可能是筛选出的一个苗头化合物或者一系列的同系物,也可能是来源于文献的化合物。但是对于高通量筛选,可能会产生离散的、多个系列的苗头化合物,这就需要选择其中一个系列继续研究,这个过程被称作“Hit to Lead”。
“Hit to Lead”过程应该注意:
- 紧密结合特定的生物活性和ADME性质
- 平行的生物学评价和“可发展性”评估至关重要
- 密集的数据矩阵
- 高自动化程度,高水平的计算分析
- 周期长短是成功的关键,需要整合体外ADME分析和计算工具
- 计算工具可以发挥重要作用
-
若想外包成功,需要CRO获取所有的化学/生物/化合物/ADME数据
一个好的先导化合物需要满足:
- 从高通量筛选得到足够理想的,多个离散系列的化合物
- 用新鲜的、纯度高的样本确证生物活性和化合物结构
- 体外活性<3μM,合适的功能活性
- 可逆性(Reversibility)
- 可行的选择性实验
- 单个化合物需要合成同系列的小化合物库确证其活性
- 需要5-10个化合物来确证选择的多样性
- 不含不需要的功能性基团或化学反应基团
- 不含毒效团
- 可修饰的化学位点
- 可追踪的物理性质
- 分子量、溶解度、极性
- 对代表性同系物可分析的ADME性质
- 尤其关注合适的口服吸收性质,静脉注射的溶解性和中枢神经系统的渗透性
- ADME问题都是易处理的
*特别注意:生物活性通常是最容易优化的性质。
先导化合物的优化
先导化合物的优化是选择一个先导化合物对其进行临床前评估,将其转化为候选药物的过程:
- 大部分时间都用来解决ADME/T问题
- 分开研究药代动力学和药效学作用持续时间可收获意想不到的益处
- 修饰先导化合物时,密切关注其物理化学性质的变化
- 对于没有选择性的化合物,多多考虑脱靶效应/毒性
- 密切关注临床前研究要求
- 获取经验的最佳途径是从实际工作中以及阅读药物研发的案例
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