• Heinrich Rueeger, Rainer Lueoend, Olivier Rogel, Jean-Michel Rondeau, Henrik Möbitz, Rainer Machauer, Laura Jacobson, Matthias Staufenbiel, Sandrine Desrayaud, and Ulf Neumann.
• Department of Global Discovery Chemistry, Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland. heinrich.rueeger@novartis.com
• J. Med. Chem. 2012 Apr 12; 55 (7): 3364-86.

AbstractStructure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.© 2012 American Chemical Society

48 keywords...

hide…