509142-48-7Relevant articles and documents
Improved Cav2.2 channel inhibitors through a gem -dimethylsulfone bioisostere replacement of a labile sulfonamide
Shao, Pengcheng P.,Ye, Feng,Chakravarty, Prasun K.,Herrington, James B.,Dai, Ge,Bugianesi, Randal M.,Haedo, Rodolfo J.,Swensen, Andrew M.,Warren, Vivien A.,Smith, McHardy M.,Garcia, Maria L.,McManus, Owen B.,Lyons, Kathryn A.,Li, Xiaohua,Green, Mitchell,Jochnowitz, Nina,McGowan, Erin,Mistry, Shruti,Sun, Shu-Yu,Abbadie, Catherine,Kaczorowski, Gregory J.,Duffy, Joseph L.
supporting information, p. 1064 - 1068 (2013/12/04)
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
Discovery of (3 S,3a R)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5- tetrahydro-2 H -benzo[ g ]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy
Meyers, Marvin J.,Arhancet, Graciela B.,Hockerman, Susan L.,Chen, Xiangyang,Long, Scott A.,Mahoney, Matthew W.,Rico, Joseph R.,Garland, Danny J.,Blinn, James. R.,Collins, Joe T.,Yang, Shengtian,Huang, Horng-Chih,McGee, Kevin F.,Wendling, Jay M.,Dietz, Jessica D.,Payne, Maria A.,Homer, Bruce L.,Heron, Marcia I.,Reitz, David B.,Hu, Xiao
experimental part, p. 5979 - 6002 (2010/11/02)
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 pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
NEW PYRIMIDINE DERIVATIVES AND THEIR USE IN THERAPY AS WELL AS THE USE OF PYRIMIDINE DERIVATIVES IN THE MANUFACTURE OF A MEDICAMENT FOR PREVENTION AND/OR TREATMENT OF ALZHEIMER’S DISEASE
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Page/Page column 135, (2008/06/13)
The present invention relates to use of compounds of formula (I) as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a process for their preparation and new intermediates used therein, as pharmaceutical ingredients fo
Modulators of serotonin receptors
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Page/Page column 50, (2010/02/11)
The present invention provides modulators of serotonin receptors, pharmaceutical compositions containing such modulators and methods for treating various diseases, conditions and disorders associated with modulation of serotonin receptors such as, for exa
