Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.

@article{Meyers2010DiscoveryO,
  title={Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.},
  author={Marvin J. Meyers and Graciela B. Arhancet and Susan Hockerman and Xiangyang Chen and Scott A. Long and Matthew W. Mahoney and Joseph R. Rico and Danny J. Garland and James R. Blinn and Joe T. Collins and Shengtian Yang and Horng-Chih Huang and K. F. Jun. Mcgee and Jay M. Wendling and Jessica D Dietz and Maria A. Payne and Bruce L. Homer and Marcia I. Heron and David B. Reitz and Xiao Hu},
  journal={Journal of medicinal chemistry},
  year={2010},
  volume={53 16},
  pages={
          5979-6002
        }
}
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the… Expand
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.
TLDR
(R)-14c was identified as a potent nonsteroidal MR antagonist 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. Expand
Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.
TLDR
Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects, and good pharmacokinetic profiles. Expand
Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists.
TLDR
Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. Expand
Design, synthesis, and structure-activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists.
TLDR
Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor, progesterone receptor (PR) and glucocorticoid receptor (GR). Expand
Synthesis of Trans- and cis-2-acetyl-3-phenyl-3,3a,4,5-tetrahydro-2H-benzo[g] Indazoles: Evaluation as Inhibitors of β-hematin Formation
Several trans- and cis-2-acetyl-3-(substituted-phenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole derivatives have been synthesised via the condensation of the appropriate exocyclic α,β-unsaturatedExpand
Aromatization and Halogenation of 3,3a,4,5‐Tetrahydro‐3‐aryl‐2‐phenyl‐2H‐benzo[g]indazole Using I2/DMSO, CuCl2/DMSO, and N‐Bromosuccinimide
The treatment of 3,3a,4,5-tetrahydro-3-aryl-2-phenyl-2H-benzo[g]indazoles 4 with I2/DMSO led to the oxidation of the five-member rings (5) as well as the iodination of N-phenyl moieties along withExpand
Synthesis of 1-[4-(1,3-diaryl-4,5-dihydro-1H-pyrazol-5-yl)-2,3,5,6-tetrafluorophenyl]piperidin-4-ols and their acrylates
Abstract(4-Hydroxypiperidin-1-yl)tetra- and -octafluorochalcones reacted with phenylhydrazine in acetic acid to give mixtures of polyfluoro-1,3,5-triaryl-4,5-dihydro-1H-pyrazoles and their O-acetylExpand
Design, synthesis and cytotoxicity evaluation of pyrazolyl pyrazoline and pyrazolyl aminopyrimidine derivatives as potential anticancer agents
In an attempt to find bio-active heterocyclic analogues, a series of novel 1-(5-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazol-1-yl)ethanones 5a–i andExpand
Syntheses and Crystal Structures of Two 2H-dibenzo[e, g]indazoles
In this paper, two 2H-dibenzo[e, g]indazoles, 6-methoxy-9-isopropoxy-2H-dibenzo[e, g]indazole(1) and 6-fluoro-9-methoxy-2H-dibenzo[e, g]indazole(2) have been one-pot synthesized from theExpand
Influence of the non-conjugated 5-position substituent of 1,3,5-triaryl-2-pyrazoline-based photosensitizers on the photophysical properties and performance of a dye-sensitized solar cell
We report the effect of the non-conjugated 5-position substituent of pyrazoline-based photosensitizers on the photophysical characteristics and performance of dye-sensitized solar cells (DSSCs). FourExpand
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