Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.已知神经营养因子（neurotrophin）家族的激素——神经生长因子（nerve growth factor，NGF）、脑源性神经营养因子（brain derived neurotrophic factor，BDNF）、神经营养因子3（neurotrophin 3，NT3）以及神经营养因子4（neurotrophin 4，NT4）——可激活原肌球蛋白受体激酶（Tropomyosin receptor kinases，Trk）家族（涵盖TrkA、TrkB与TrkC）。此外，疼痛相关研究中针对TrkA激酶通路的抑制作用已通过NGF抗体他尼单抗（tanezumab）完成临床验证，这使得开发TrkA小分子抑制剂的相关工作受到广泛关注。进一步而言，具备可接受安全性特征的Trk抑制剂需要极低的脑内暴露量。本文探讨了两类强效、高选择性、外周限制性、具有明确药效且耐受性良好的泛Trk抑制剂系列，成功获得3种符合候选化合物质量标准的分子10b、13b与19。预测显示，上述3种化合物在人体内的代谢清除率较低，且其代谢途径不涉及醛氧化酶催化的反应，由此解决了当前泛Trk开发候选化合物PF-06273340所关联的潜在清除率预测风险问题。