(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: a wingless beta-catenin agonist that increases bone formation rate

  • J Med Chem. 2009 Nov 26;52(22):6962-5. doi: 10.1021/jm9014197.
Jeffrey C Pelletier  1 ,  Joseph T Lundquist 4th ,  Adam M Gilbert ,  Nipa Alon ,  Frederick J Bex ,  Bheem M Bhat ,  Mattew G Bursavich ,  Valerie E Coleburn ,  Luciana A Felix ,  Daniel M Green ,  Paula Green ,  Diane B Hauze ,  Yogendra P Kharode ,  Ho-Sun Lam ,  Susan R Lockhead ,  Ronald L Magolda ,  Jeanne J Matteo ,  John F Mehlmann ,  Colleen Milligan ,  Richard J Murrills ,  Jennifer Pirrello ,  Sally Selim ,  Michael C Sharp ,  Ray J Unwalla ,  Matthew D Vera ,  Jay E Wrobel ,  Paul Yaworsky ,  Peter V N Bodine
Affiliations
  • 1. Chemical Sciences, Drug Safety & Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. [email protected]
PMID: 19856966 DOI: 10.1021/jm9014197
Abstract

A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.

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