Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist

Brown, Angus R.; Bosies, Michael; Cameron, H.A.; Clark, John K.; Cowley, Angela; Craighead, Mark; Elmore, Moira A.; Firth, Alistair; Goodwin, Richard; Goutcher, Susan; Grant, Emma J.; Grassie, Morag A.; Grove, Simon J. A.; Hamilton, Niall M.; Hampson, Hannah; Hillier, Alison; Ho, Koc-Kan; Kiczun, Michael; Kingsbury, Celia; Kultgen, Steven G.; Littlewood, Peter; 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 Ann; Weston, Mark A.

doi:10.1016/j.bmcl.2010.11.054

Cited by 7 publications

(10 citation statements)

References 10 publications

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“…However compound 1 displayed a poor selectivity profile with a higher binding affinity to both PR (p K i =6.9) and GR (p K i =7.2, Table ). These results are in agreement with previous published data of this structure class as MR, GR and PR ligands …”

Section: Resultssupporting

confidence: 94%

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Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

et al. 2016

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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 pK =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 pK =7.3. Two protein-ligand X-ray structures were determined, confirming the hypothesized binding mode for the designed compounds.

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Section: Resultssupporting

confidence: 94%

“…Subsequent testing in a functional assay demonstrated that the compound was a full MR antagonist. However, this class of ligands have reported activity for several oxosteroid receptors . By combining SAR exploration and X‐ray structure determination we exploited differences in the ligand binding pockets to improve selectivity toward MR.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

et al. 2016

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“…1). OrgA is a member of a compound class described as glucocorticoid receptor antagonists (28) but is a relatively potent PR partial agonist whose activity is described in a recent article (26). Bacteria were lysed in buffer A (50 mM Tris, pH 7.8, 250 mM NaCl, 10% glycerol, 10 mM ␤-mercaptoethanol) with 0.4 mM Pefablock (Roche Applied Science) and 50 M OrgA and purified on nickel nitrilotriacetic acid.…”

Section: Methodsmentioning

confidence: 99%

“…1), with a previously disclosed mixed PR profile (PR agonist EC 50 0.66 nM with 47% efficacy, PR antagonist EC 50 0.61 nM with 38% (28) …”

Section: Modulation Of the Progesterone Receptor (Pr)mentioning

confidence: 99%

X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11β-Substituted Steroids

Lusher

Raaijmakers

Vu-Pham

et al. 2012

Journal of Biological Chemistry

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Background: Understanding the molecular basis for the mixed profiles of progesterone receptor (PR) ligands will benefit future drug design. Results: Two differing mechanisms for the induction of mixed profiles by 11␤-steroids are described. Conclusion: Subtle electrostatic and steric factors explain the differing PR activities of 11␤-steroids. Significance: These observations will impact future drug-design strategies for PR and potentially other nuclear receptors.

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“…Our earlier work on the discovery and optimization of a selective nonsteroidal glucocorticoid receptor antagonist (23) resulted in the synthesis of a number of moderately active PR modulators, including OrgA, OrgB, and OrgC (see Table 1). Interestingly, OrgA is a partial PR agonist despite high chemical similarity to OrgB and OrgC, which are both full PR antagonists.…”

mentioning

confidence: 99%

Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

Lusher¹,

Raaijmakers²,

Vu-Pham³

et al. 2011

Journal of Biological Chemistry

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The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.

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Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist

Cited by 7 publications

References 10 publications

Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11β-Substituted Steroids

Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

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