N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation

  • J Med Chem. 2009 May 14;52(9):2794-8. doi: 10.1021/jm801583j.
Alexandra A Nirschl  1 ,  Yan Zou ,  Stanley R Krystek Jr ,  James C Sutton ,  Ligaya M Simpkins ,  John A Lupisella ,  Joyce E Kuhns ,  Ramakrishna Seethala ,  Rajasree Golla ,  Paul G Sleph ,  Blake C Beehler ,  Gary J Grover ,  Donald Egan ,  Aberra Fura ,  Viral P Vyas ,  Yi-Xin Li ,  John S Sack ,  Kevin F Kish ,  Yongmi An ,  James A Bryson ,  Jack Z Gougoutas ,  John DiMarco ,  Robert Zahler ,  Jacek Ostrowski ,  Lawrence G Hamann
Affiliations
  • 1. Discovery Chemistry, Analytical Research & Development, Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA.
PMID: 19351168 DOI: 10.1021/jm801583j
Abstract

A novel selective Androgen Receptor Modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.