Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
ChemMedChem. 2018 Dec 6;13(23):2530-2545. doi: 10.1002/cmdc.201800549. Epub 2018 Nov 20.
Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene receptor 1 (CysLT R) antagonist pranlukast on the farnesoid X receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub-nanonmolar potency. The resulting FXR modulators lack any activity on CysLT R and are characterized by high selectivity, high metabolic stability, and low toxicity. With their favorable in vitro profile, these SOSA-derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.
选择性优化侧活性（SOSA）为早期药物发现提供了另一种途径，可能为具有理想特性的生物活性新化学实体提供快速通道。SOSA 的目的是通过结构修饰逆转药物的副作用，并设计出药物的原始主要作用。我们发现半胱氨酰白三烯受体 1（CysLT R）拮抗剂普仑司特对法尼醇 X 受体（FXR）具有中等程度的副作用。药物的系统结构修饰使药物对 FXR 的部分激动作用显著优化至亚纳摩尔效力。由此产生的 FXR 调节剂对 CysLT R 没有任何活性，其特点是高选择性、高代谢稳定性和低毒性。这些源自 SOSA 的 FXR 调节剂具有良好的体外特性，构成了一种新的 FXR 配体化学类型，似乎适合进一步的临床前评估。
