- Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mG
-
This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previo
- Bollinger, Sean R.,Engers, Darren W.,Panarese, Joseph D.,West, Mary,Engers, Julie L.,Loch, Matthew T.,Rodriguez, Alice L.,Blobaum, Anna L.,Jones, Carrie K.,Thompson Gray, Analisa,Conn, P. Jeffrey,Lindsley, Craig W.,Niswender, Colleen M.,Hopkins, Corey R.
-
p. 342 - 358
(2018/10/20)
-
- SUBSTITUTED TRICYCLIC 1,4-BENZODIAZEPINONE DERIVATIVES AS ALLOSTERIC MODULATORS OF GROUP II METABOTROPIC GLUTAMATE RECEPTORS
-
The present invention provides novel tricyclic 1,4-benzodiazepinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) and the pharmaceutical compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. The tricyclic 1,4-benzodiazepinone derivatives of formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. The present invention further provides tricyclic 1,4-benzodiazepinone derivatives of formula (I) that are modulators of metabotropic glutamate receptors (mGluRs), particularly positive allosteric modulators of mGluRs, and more specifically positive allosteric modulators of mGluR3. (I)
- -
-
-
- Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis
-
A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ~100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ~90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.
- Hong, W. David,Gibbons, Peter D.,Leung, Suet C.,Amewu, Richard,Stocks, Paul A.,Stachulski, Andrew,Horta, Pedro,Cristiano, Maria L. S.,Shone, Alison E.,Moss, Darren,Ardrey, Alison,Sharma, Raman,Warman, Ashley J.,Bedingfield, Paul T. P.,Fisher, Nicholas E.,Aljayyoussi, Ghaith,Mead, Sally,Caws, Maxine,Berry, Neil G.,Ward, Stephen A.,Biagini, Giancarlo A.,O’Neill, Paul M.,Nixon, Gemma L.
-
p. 3703 - 3726
(2017/05/19)
-
- RING-FUSED COMPOUND
-
The present invention relates to a compound that has URAT1 inhibitory action, and a URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition comprising the compound. More specifically, the present invention relates to a compound represented by Formula (I) below. [in the formula, R1 is -Q1-A1 and the like; ---- is a double bond or a single bond; when ---- is a double bond, W1 is a nitrogen atom or a group represented by the general formula: =C(Ra)-, and W2 is a nitrogen atom or a group represented by the general formula: =C(Rb) -; when ---- is a single bond, W1 is a group represented by the general formula: -C(Raa)(Rab)- or a group represented by the general formula: -(C=O) -, and W2 is a group represented by the general formula: C(Rba)(Rbb)-, a group represented by the general formula: - (C=O) - or a group represented by the general formula: -N(Rbc)-; W3, W4 and W5 are each independently a nitrogen atom or a methine group and the like that may have a substituent; X is a single bond, an oxygen atom and the like; Y is a single bond or (CRYiRYi')n; and Z is a hydroxyl group or COOR2 and the like.
- -
-
-
- PHTALAZINE DERIVATIVES AS JAK1 INHIBITORS
-
JAK1 inhibitors of structural formula (I), wherein Ar1, Ar2, Q, W, X, Y, and Z are defined in the specification, pharmaceutically acceptable salts thereof, compositions thereof, and use of the compounds and compositions for treating diseases. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases.
- -
-
Page/Page column 53
(2012/04/04)
-
- INDAZOLE COMPOUNDS USEFUL AS KETOHEXOKINASE INHIBITORS
-
The present invention is directed to substituted indazole compounds, pharmaceutical compositions of these compounds and methods of use thereof. The compounds of the present invention are ketohexokinase (KHK) inhibitors, useful for treating or ameliorating a KHK mediated metabolic disorders and/or diseases such as obesity, Type II diabetes mellitus and Metabolic Syndrome X.
- -
-
-
- NOVEL KINASE MODULATORS
-
The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.
- -
-
-
- Indazole derivatives with 5-HT2 receptor activity
-
A chemical compound of formula (I) wherein R1 to R3 are independently selected from hydrogen and alkyl; R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, monoalkylamino, di
- -
-
-
- Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors
-
Aryldihydropyridazinones and aryldimethylpyrazolones with 2-benzyl vinylogous amide substituents have been identified as potent PDE3B subtype selective inhibitors. Dihydropyridazinone 8a (PDE3B IC50=0.19 nM, 3A IC50=1.3 nM) was selec
- Edmondson, Scott D.,Mastracchio, Anthony,He, Jiafang,Chung, Christine C.,Forrest, Michael J.,Hofsess, Scott,MacIntyre, Euan,Metzger, Joseph,O'Connor, Naphtali,Patel, Kajal,Tong, Xinchun,Tota, Michael R.,Van Der Ploeg, Lex H. T.,Varnerin, Jeff P.,Fisher, Michael H.,Wyvratt, Matthew J.,Weber, Ann E.,Parmee, Emma R.
-
p. 3983 - 3987
(2007/10/03)
-