- Novel N-linked aminopiperidine-based gyrase inhibitors with improved hERG and in vivo efficacy against mycobacterium tuberculosis
-
DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.
- Hameed P, Shahul,Patil, Vikas,Solapure, Suresh,Sharma, Umender,Madhavapeddi, Prashanti,Raichurkar, Anandkumar,Chinnapattu, Murugan,Manjrekar, Praveena,Shanbhag, Gajanan,Puttur, Jayashree,Shinde, Vikas,Menasinakai, Sreenivasaiah,Rudrapatana, Suresh,Achar, Vijayashree,Awasthy, Disha,Nandishaiah, Radha,Humnabadkar, Vaishali,Ghosh, Anirban,Narayan, Chandan,Ramya,Kaur, Parvinder,Sharma, Sreevalli,Werngren, Jim,Hoffner, Sven,Panduga, Vijender,Kumar, C. N. Naveen,Reddy, Jitendar,Kumar Kn, Mahesh,Ganguly, Samit,Bharath, Sowmya,Bheemarao, Ugarkar,Mukherjee, Kakoli,Arora, Uma,Gaonkar, Sheshagiri,Coulson, Michelle,Waterson, David,Sambandamurthy, Vasan K.,De Sousa, Sunita M.
-
p. 4889 - 4905
(2014/07/07)
-
- NOVEL COMPOUNDS AS ANTAGONISTS OR INVERSE AGONISTS FOR OPIOID RECEPTORS
-
This invention relates to novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy.
- -
-
Page/Page column 95
(2010/09/07)
-
- CHEMOKINE RECEPTOR BINDING COMPOUNDS
-
The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR4 or CCR5. In one aspect, these compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
- -
-
Page/Page column 50-51
(2010/11/26)
-
- NOVEL TRIAZOLOPYRIDINE COMPOUNDS
-
This invention is directed generally to triazolopyridine compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygenase activity. Such triazolopyridine include compounds generally corresponding in structure to the following formula (I): wherein R
- -
-
Page/Page column 75; 76
(2008/06/13)
-
- NOVEL TRIAZOLOPYRIDINE COMPOUNDS FOR THE TREATMENT OF INFLAMMATION
-
This invention is directed generally to triazolopyridine compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygenase activity. Such triazolopyridine include compounds generally corresponding in structure to the following formula (I): Wherein R1, R2, R3, R4, and R5are as defined in this specification. This invention also is directed to compositions of such triazolopyridines (particularly pharmaceutical compositions), intermediates for the syntheses of such triazolopyridines, methods for making such triazolopyridines, and methods for treating (including preventing) conditions (typically pathological conditions) associated with p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity.
- -
-
Page/Page column 91
(2008/06/13)
-
- PROCESSES FOR THE PREPARATION OF PYRAZOLO[1,5-a]-1,3,5-TRIAZINES AND INTERMEDIATES THEREOF
-
The present invention provides novel processes and intermediates for preparing corticotropin releasing factor (CRF) receptor antagonists having the structure below which are useful in treating CRF-related disorders such as anxiety and depression.
- -
-
Page/Page column 38; 39
(2010/02/11)
-