Identification of Two Novel, Potent, Low-Liability Antinociceptive Compounds from the Direct In Vivo Screening of a Large Mixture-Based Combinatorial Library
Identification of Two Novel, Potent, Low-Liability Antinociceptive Compounds from the Direct In Vivo Screening of a Large Mixture-Based Combinatorial Library
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DOI：
10.1208/s12248-010-9191-3
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发表时间：
2010-09-01
期刊：
影响因子：
4.5
通讯作者：
Houghten, Richard A.
中科院分区：
文献类型：
--
作者：
Reilley, Kate J.;Giulianotti, Marc;Houghten, Richard A.
合成组合方法现在可以很容易地产生数十万种单独的化合物，但在体内单独筛选每一种显然是不切实际的。我们的理论是，在发现阶段对基于混合物的组合文库进行直接体内测试将能够识别具有理想抗伤害特性的新的单个化合物，同时消除许多吸收、分布、代谢或药代动力学性质较差的化合物。TPI 1346小分子组合文库由120个混合物组成，它们分别来自吡咯烷双环胍核支架前三位的26个官能团和第四位的42个官能团，总计738,192个化合物。使用小鼠55℃温水回尾试验对这120种混合物进行活体筛选，以鉴定产生抗伤害作用的混合物。根据这些数据，合成了两个完全定义的化合物(TPI1818-1818101和TPI1818-109)。对这些受试者进行了抗伤害性、呼吸、运动和条件性位置偏爱效应的检测。戒断尾巴实验一致显示，具有明显镇痛活性的混合物可被非选择性阿片拮抗剂纳洛酮阻断。基于这些结果，TPI 1818-101和1818-109的合成和测试显示出剂量依赖的抗伤害效应，分别比分别被Mu或Mu和Kappa阿片受体选择性拮抗剂拮抗的吗啡强3~5倍。1818101和1818109年都没有发生明显的呼吸抑制、过度运动或条件性位置偏爱。大型的、高度多样化的基于混合物的文库可以在体内直接筛选以识别单独的化合物，这可能会加速有前景的治疗药物的开发。
Synthetic combinatorial methods now make it practical to readily produce hundreds of thousands of individual compounds, but it is clearly impractical to screen each separately in vivo. We theorized that the direct in vivo testing of mixture-based combinatorial libraries during the discovery phase would enable the identification of novel individual compounds with desirable antinociceptive profiles while simultaneously eliminating many compounds with poor absorption, distribution, metabolism, or pharmacokinetic properties. The TPI 1346 small-molecule combinatorial library is grouped in 120 mixtures derived from 26 functionalities at the first three positions and 42 functionalities at the fourth position of a pyrrolidine bis-cyclic guanidine core scaffold, totaling 738,192 compounds. These 120 mixtures were screened in vivo using the mouse 55 degrees C warm water tail-withdrawal assay to identify mixtures producing antinociception. From these data, two fully defined individual compounds (TPI 1818101 and TPI 1818-109) were synthesized. These were examined for antinociceptive, respiratory, locomotor, and conditioned place preference effects. The tail-withdrawal assay consistently demonstrated distinctly active mixtures with analgesic activity that was blocked by pretreatment with the non-selective opioid antagonist, naloxone. Based on these results, synthesis and testing of TPI 1818-101 and 1818-109 demonstrated a dose-dependent antinociceptive effect three to five times greater than morphine that was antagonized by mu- or mu- and kappa-opioid receptor selective antagonists, respectively. Neither 1818101 nor 1818-109 produced significant respiratory depression, hyperlocomotion, or conditioned place preference. Large, highly diverse mixture-based libraries can be screened directly in vivo to identify individual compounds, potentially accelerating the development of promising therapeutics.