474806-63-8Relevant academic research and scientific papers
Heteroatom insertion into 3,4-dihydro-1 H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase
Grombein, Cornelia M.,Hu, Qingzhong,Rau, Sabrina,Zimmer, Christina,Hartmann, Rolf W.
supporting information, p. 788 - 796 (2015/02/19)
Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2. 2 μM).
Inhibitors of the Human Aldosterone Sythase CYP11B2
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Page/Page column 33, (2011/05/16)
The invention provides compounds of the general formula (I) which are inhibitors of the human aldosterone synthase, and also pharmaceutical compositions containing these compounds, and a method of treating of hyperaldosteronism and/or disorders or diseases that are mediated by 11β-hydroxylase (CYP11B1) with these compounds.
6-PYRIDIN-3-YL-3,4-DIHYDRO-1H-QUINOLIN-2-ONE DERIVATIVES AND RELATED COMPOUNDS AS INHIBITORS OF THE HUMAN ALDOSTERONE SYNTHASE CYP11B2
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Page/Page column 49-50, (2010/01/29)
The invention provides compounds of the general formula (I) which are inhibitors of the human aldosterone synthase, and also pharmaceutical compositions containing these compounds, and the use of these compounds and other heteroaryl substituted quinolinone derivatives for the treatment of hyperaldosteronism and/or disorders or diseases that are mediated by 11 β-hydroxylase (CYP11 B1 ).
Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors
Varnes, Jeffrey G.,Wacker, Dean A.,Jacobson, Irina C.,Quan, Mimi L.,Ellis, Christopher D.,Rossi, Karen A.,He, Ming Y.,Luettgen, Joseph M.,Knabb, Robert M.,Bai, Steven,He, Kan,Lam, Patrick Y.S.,Wexler, Ruth R.
, p. 6481 - 6488 (2008/03/18)
A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding Kis, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
