1246765-59-2Relevant academic research and scientific papers
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
Casimiro-Garcia, Agustin,Piotrowski, David W.,Ambler, Catherine,Arhancet, Graciela B.,Banker, Mary Ellen,Banks, Tereece,Boustany-Kari, Carine M.,Cai, Cuiman,Chen, Xiangyang,Eudy, Rena,Hepworth, David,Hulford, Catherine A.,Jennings, Sandra M.,Loria, Paula M.,Meyers, Marvin J.,Petersen, Donna N.,Raheja, Neil K.,Sammons, Matthew,She, Li,Song, Kun,Vrieze, Derek,Wei, Liuqing
, p. 4273 - 4288 (2014/06/09)
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.
4, 5-DIHYDRO-LH-PYRAZOLE COMPOUNDS AND THEIR PHARMACEUTICAL USES
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Page/Page column 80-81, (2010/11/03)
Mineralocorticoid receptor antagonists (MRa), pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, diabetic nephropathy and hypertension in mammals, including humans.
