Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active gamma-secretase modulators

作者：Pettersson Martin^*; Johnson Douglas S; Subramanyam Chakrapani; Bales Kelly R; Ende Christopher W Am; Fish Benjamin A; Green Michael E; Kauffman Gregory W; Lira Ricardo; Mullins Patrick B; Navaratnam Thayalan; Sakya Subas M; Stiff Cory M; Tran Tuan P; Vetelino Beth C; Xie Longfei; Zhang Liming; Pustilnik Leslie R; Wood Kathleen M; O'Donnell Christopher J

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(8): 2906-2911.

DOI：10.1016/j.bmcl.2012.02.059

• Alzheimer's disease
• gamma-Secretase modulators

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as gamma-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain A beta 42 lowering activity at 100 mg/kg po dose.

• 出版日期2012-4-15