title: Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Anneli
authors.identifier: 0000-0001-5829-3836
authors.initials: A
authors.lastname: Nordqvist
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Gavin
authors.initials: G
authors.lastname: O'Mahony
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Fridén-Saxin
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Marlene
authors.initials: M
authors.lastname: Fredenwall
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hogner
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Granberg
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Aagaard
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bäckström
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Gunnarsson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Tim
authors.initials: T
authors.lastname: Kaminski
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Dellsén
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hansson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Hansson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Ivarsson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Karlsson
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Krister
authors.initials: K
authors.lastname: Bamberg
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Majlis
authors.initials: M
authors.lastname: Hermansson
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Jennie
authors.initials: J
authors.lastname: Georgsson
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Lindmark
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid
keywords: NR3C2; drug design; macrocycles; nuclear hormone receptors; structure-based drug design