Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity
The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X-ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced-fit hypothesis that required movement of the Met852 side chain. An improvement in MR selectivity of 11- to 79-fold over PR and 23- to 234-fold over GR was obtained. Given the U-shaped binding conformation, macrocyclizations were explored, yielding a macrocycle that bound to MR with pKi=7.3. Two protein–ligand X-ray structures were determined, confirming the hypothesized binding mode for the designed compounds.
Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Brown, Angus R.,Bosies, Michael,Cameron, Helen,Clark, John,Cowley, Angela,Craighead, Mark,Elmore, Moira A.,Firth, Alistair,Goodwin, Richard,Goutcher, Susan,Grant, Emma,Grassie, Morag,Grove, Simon J.A.,Hamilton, Niall M.,Hampson, Hannah,Hillier, Alison,Ho, Koc-Kan,Kiczun, Michael,Kingsbury, Celia,Kultgen, Steven G.,Littlewood, Peter T.A.,Lusher, Scott J.,MacDonald, Susan,McIntosh, Lorraine,McIntyre, Theresa,Mistry, Ashvin,Morphy, J. Richard,Nimz, Olaf,Ohlmeyer, Michael,Pick, Jack,Rankovic, Zoran,Sherborne, Brad,Smith, Alasdair,Speake, Michael,Spinks, Gayle,Thomson, Fiona,Watson, Lynn,Weston, Mark
scheme or table
p. 137 - 140
(2011/02/27)
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