Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

  • Bioorg Med Chem Lett. 2013 Oct 1;23(19):5442-7. doi: 10.1016/j.bmcl.2013.06.089.
James E Sheppeck 2nd  1 ,  John L Gilmore ,  Hai-Yun Xiao ,  T G Murali Dhar ,  David Nirschl ,  Arthur M Doweyko ,  Jack S Sack ,  Martin J Corbett ,  Mary F Malley ,  Jack Z Gougoutas ,  Lorraine Mckay ,  Mark D Cunningham ,  Sium F Habte ,  John H Dodd ,  Steven G Nadler ,  John E Somerville ,  Joel C Barrish
Affiliations
PMID: 23953070 DOI: 10.1016/j.bmcl.2013.06.089
Abstract

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.

Keywords
Dissociated GR inhibitors; GR agonist; Glucocortocoid receptor.