Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors

详细信息    查看全文

• 作者：Thomas J. Greshock^a ; ^{thomas_greshock@merck.com" class="auth_mail" title="E-mail the corresponding author} ; John M. Sanders^b ; ^{john_sanders@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Robert E. Drolet^c ; Hemaka A. Rajapakse^a ; Ronald K. Chang^a ; Boyoung Kim^a ; Vanessa L. Rada^a ; Heather E. Tiscia^a ; Hua Su^d ; Ming-Tain Lai^e ; Sylvie M. Sur^e ; Rosa I. Sanchez^f ; Mark T. Bilodeau^a ; John J. Renger^c ; Jonathan T. Kern^c ; John A. McCauley^a
• 关键词：LRRK2 ; Parkinson&rsquo ; s disease ; Leucine rich repeat kinase ; CNS ; Kinase
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：26
• 期：11
• 页码：2631-2635
• 全文大小：1264 K

文摘

Familial Parkinson’s disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson’s disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.