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

  • Bioorg Med Chem Lett. 2012 Apr 15;22(8):2906-11. doi: 10.1016/j.bmcl.2012.02.059.
Martin Pettersson  1 ,  Douglas S Johnson ,  Chakrapani Subramanyam ,  Kelly R Bales ,  Christopher W am Ende ,  Benjamin A Fish ,  Michael E Green ,  Gregory W Kauffman ,  Ricardo Lira ,  Patrick B Mullins ,  Thayalan Navaratnam ,  Subas M Sakya ,  Cory M Stiff ,  Tuan P Tran ,  Beth C Vetelino ,  Longfei Xie ,  Liming Zhang ,  Leslie R Pustilnik ,  Kathleen M Wood ,  Christopher J O'Donnell
Affiliations
  • 1. Neuroscience Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, USA. [email protected]
PMID: 22429469 DOI: 10.1016/j.bmcl.2012.02.059
Abstract

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-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 Aβ42 lowering activity at 100 mg/kg po dose.