903886-71-5Relevant articles and documents
3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Blaser, Adrian,Conole, Daniel,Franzblau, Scott G.,Lotlikar, Manisha U.,Cooper, Christopher B.,Upton, Anna M.,Denny, William A.,Palmer, Brian D.
supporting information, p. 1292 - 1307 (2019/02/25)
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
6,7-DIHYDRO-5H-PYRROLO[3,4-B]PYRIDIN-5-ONE ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR
-
Paragraph 0302-0303, (2017/07/14)
The present invention is directed to 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.
PYRROLIDINONE DERIVATIVES AS GPR119 MODULATORS FOR THE TREATMENT OF DIABETES, OBESITY, DYSLIPIDEMIA AND RELATED DISORDERS
-
Paragraph 0328; 0329, (2014/04/18)
The present invention relates to pyrrolidinone derivatives. The pyrrolidinone derivatives are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to t
PYRROLIDINONE DERIVATIVES AS GPR119 MODULATORS FOR THE TREATMENT OF DIABETES, OBESITY, DYSLIPIDEMIA AND RELATED DISORDERS
-
Page/Page column 65; 67, (2014/05/07)
The present invention relates to pyrrolidinone derivatives of formula (I). The pyrrolidinone derivatives of formula (I) are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of pyrrolidinone derivatives as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.
CHEMICAL COMPOUNDS
-
, (2012/01/15)
The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein Het1, X, R1, R2, R3, R4 and R5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain
NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
-
Page/Page column 53, (2008/06/13)
The present invention relates to compounds of formula (I), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
Synthesis and structure-activity relationships of N-{3-[2-(4-alkoxyphenoxy) thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors
Gu, Yu Gui,Weitzberg, Moshe,Clark, Richard F.,Xu, Xiangdong,Li, Qun,Zhang, Tianyuan,Hansen, T. Matthew,Liu, Gang,Xin, Zhili,Wang, Xiaojun,Wang, Rongqi,McNally, Teresa,Camp, Heidi,Beutel, Bruce A.,Sham, Hing L.
, p. 3770 - 3773 (2007/10/03)
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50 1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
