Discovery and optimization of substituted 1-(1-phenyl-1H-pyrazol-3-yl)methanamines as potent and efficacious type II calcimimetics

  • J Med Chem. 2009 Nov 12;52(21):6535-8. doi: 10.1021/jm9012278.
Steve F Poon  1 ,  David J St Jean Jr ,  Paul E Harrington ,  Charles Henley 3rd ,  James Davis ,  Sean Morony ,  Fred D Lott ,  Jeff D Reagan ,  Jenny Ying-Lin Lu ,  Yuhua Yang ,  Christopher Fotsch
Affiliations
PMID: 19835382 DOI: 10.1021/jm9012278
Abstract

Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure-activity relationships of various substituted heterocycles and their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.