Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series

Jason M Cox; Hong D Chu; Christine Yang; Hong C Shen; Zhicai Wu; Jaume Balsells; Alejandro Crespo; Patricia Brown; Beata Zamlynny; Judyann Wiltsie; Joseph Clemas; Jack Gibson; Lisa Contino; JeanMarie Lisnock; Gaochao Zhou; Margarita Garcia-Calvo; Thomas Bateman; Ling Xu; Xinchun Tong; Martin Crook; Peter Sinclair

doi:10.1016/j.bmcl.2014.02.057

Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1681-4. doi: 10.1016/j.bmcl.2014.02.057. Epub 2014 Mar 1.

Authors

Jason M Cox¹, Hong D Chu², Christine Yang², Hong C Shen², Zhicai Wu², Jaume Balsells³, Alejandro Crespo⁴, Patricia Brown⁵, Beata Zamlynny⁵, Judyann Wiltsie⁶, Joseph Clemas⁶, Jack Gibson⁶, Lisa Contino⁶, JeanMarie Lisnock⁶, Gaochao Zhou⁶, Margarita Garcia-Calvo⁶, Thomas Bateman⁷, Ling Xu⁷, Xinchun Tong⁷, Martin Crook⁵, Peter Sinclair²

Affiliations

¹ Department of Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: jason_cox@merck.com.
² Department of Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
³ Department of Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
⁴ Department of Chemistry Modeling & Informatics, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
⁵ Department of Cardiovascular Diseases, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
⁶ Department of In Vitro Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
⁷ Department of Drug Metabolism, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

PMID: 24630411
DOI: 10.1016/j.bmcl.2014.02.057

Abstract

Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.

Keywords: Hypertension; Lipophilic ligand efficiency; Mineralocorticoid receptor antagonist; Oxazolidinedione.

MeSH terms

Amides / chemistry*
Animals
Dose-Response Relationship, Drug
Heterocyclic Compounds / chemistry*
Humans
Microsomes, Liver
Mineralocorticoid Receptor Antagonists / chemical synthesis
Mineralocorticoid Receptor Antagonists / chemistry
Mineralocorticoid Receptor Antagonists / pharmacology*
Molecular Structure
Oxazoles / chemical synthesis
Oxazoles / chemistry
Oxazoles / pharmacology*
Rats
Receptors, Mineralocorticoid / metabolism*
Structure-Activity Relationship

Substances

Amides
Heterocyclic Compounds
Mineralocorticoid Receptor Antagonists
Oxazoles
Receptors, Mineralocorticoid