Wurtz Nicholas R, Johnson James A, Viet Andrew, Shirude Pravin S, Baligar Vishweshwaraiah, Madduri Sudhakara, Cheney Daniel L, Park Hyunsoo, Lupisella John A, Hsu Mei-Yin, Abousleiman Mojgan, Galella Michael A, Aulakh Darpandeep, Dierks Elizabeth A, Garcia Ricardo A, Ostrowski Jacek, Kick Ellen K, Wexler Ruth R
Bristol Myers Squibb Research and Development, Princeton, New Jersey 08543, United States.
Biocon Bristol Myers Squibb R&D Center, Bangalore-560099, India.
ACS Med Chem Lett. 2022 May 25;13(6):943-948. doi: 10.1021/acsmedchemlett.2c00079. eCollection 2022 Jun 9.
Formyl peptide receptor 2 (FPR2) agonists have shown efficacy in inflammatory-driven animal disease models and have the potential to treat a range of diseases. Many reported synthetic agonists contain a phenylurea, which appears to be necessary for activity in the reported chemotypes. We set out to find isosteres for the phenylurea and focused our efforts on heteroaryl rings. The wide range of potencies with heterocyclic isosteres demonstrates how electronic effects of the heteroatom placement impact molecular recognition. Herein, we report our discovery of benzimidazole and aminophenyloxadiazole FPR2 agonists with low nanomolar activity.
甲酰肽受体2（FPR2）激动剂已在炎症驱动的动物疾病模型中显示出疗效，并且有治疗一系列疾病的潜力。许多报道的合成激动剂含有苯基脲，这似乎是所报道化学类型中活性所必需的。我们着手寻找苯基脲的电子等排体，并将工作重点放在杂芳环上。杂环电子等排体的广泛效价表明了杂原子位置的电子效应如何影响分子识别。在此，我们报告我们发现的具有低纳摩尔活性的苯并咪唑和氨基苯基恶二唑FPR2激动剂。
