2. Academic Validation
  3. Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors

Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors

  • Bioorg Med Chem Lett. 2018 May 15;28(9):1615-1620. doi: 10.1016/j.bmcl.2018.03.045.
Xiao Ding 1,  Luigi Piero Stasi 1,  Ming-Hsun Ho 2,  Baowei Zhao 1,  Hailong Wang 1,  Kai Long 1,  Qiongfeng Xu 1,  Yingxia Sang 1,  Changhui Sun 1,  Huan Hu 1,  Haihua Yu 1,  Zehong Wan 1,  Lizhen Wang 1,  Colin Edge 3,  Qian Liu 2,  Yi Li 2,  Kelly Dong 2,  Xiaoming Guan 1,  F David Tattersall 1,  Alastair D Reith 4,  Feng Ren 5
Affiliations

Affiliations

  • 1 Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China.
  • 2 Platform Technology Sciences, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China.
  • 3 Platform Technology Sciences, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, UK.
  • 4 Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, UK.
  • 5 Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China. Electronic address: 2648666968@qq.com.
PMID: 29588215 DOI: 10.1016/j.bmcl.2018.03.045
Abstract

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration.

Keywords

CNS penetration; Kinase selectivity; LRRK2; Parkinson’s disease; Pyrrolo[2,3-d]pyrimidine.

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