189956-41-0Relevant articles and documents
Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure
Meng, Wei,Pi, Zulan,Brigance, Robert,Rossi, Karen A.,Schumacher, William A.,Bostwick, Jeffrey S.,Gargalovic, Peter S.,Onorato, Joelle M.,Luk, Chiuwa E.,Generaux, Claudia N.,Wang, Tao,Wexler, Ruth R.,Finlay, Heather J.
supporting information, p. 18102 - 18113 (2021/12/13)
This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound 2 showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites in vitro. In this article, we extended the structure–activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.
COMPOUNDS, COMPOSITIONS AND METHODS
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Paragraph 0218; 0315, (2019/02/25)
The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.
CETP INHIBITORS
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Page/Page column 41, (2008/06/13)
Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
SAR in the alkoxy lactone series: The discovery of DFP, a potent and orally active COX-2 inhibitor
Leblanc,Roy,Boyce,Brideau,Chan,Charleson,Gordon,Grimm,Guay,Leger,Li,Riendeau,Visco,Wang,Webb,Xu,Prasit
, p. 2207 - 2212 (2007/10/03)
Extensive SAR has been established in the alkoxy lactone series and this has lead to the discovery of DFP (5,5-dimethyl-3-(2-propoxy)-4- methanesulfonylphenyl)-2(5H)-furanone), a potent COX-2 inhibitor exhibiting in vivo efficacy in all models studied.
