title: Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist.
abstract: A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na(+)/K(+) ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na(+)/K(+) ratio and demonstrated this novel compound acts as an MR antagonist.
authors.affiliation: Pfizer Worldwide Research and Development , 200 CambridgePark Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Agustin
authors.initials: A
authors.lastname: Casimiro-Garcia
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.forename: Catherine
authors.initials: C
authors.lastname: Ambler
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Arhancet
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Banker
authors.forename: Tereece
authors.initials: T
authors.lastname: Banks
authors.forename: Carine M
authors.initials: CM
authors.lastname: Boustany-Kari
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Chen
authors.forename: Rena
authors.initials: R
authors.lastname: Eudy
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Hulford
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Jennings
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
authors.forename: Donna N
authors.initials: DN
authors.lastname: Petersen
authors.forename: Neil K
authors.initials: NK
authors.lastname: Raheja
authors.forename: Matthew
authors.initials: M
authors.lastname: Sammons
authors.forename: Li
authors.initials: L
authors.lastname: She
authors.forename: Kun
authors.initials: K
authors.lastname: Song
authors.forename: Derek
authors.initials: D
authors.lastname: Vrieze
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D055808:Drug Discovery; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011188:Potassium / Q000652:urine; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000737:chemistry; D012964:Sodium / Q000652:urine; D013329:Structure-Activity Relationship
chemical_list: C000590372:6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid; D000451:Mineralocorticoid Receptor Antagonists; D009539:Nicotinic Acids; D011720:Pyrazoles; D018161:Receptors, Mineralocorticoid; D012964:Sodium; D011188:Potassium