- Synthesis of pyrazole-carboxamides and pyrazole-carboxylic acids derivatives: Simple methods to access powerful building blocks
-
Hybrid systems containing pyrazole moiety show a wide spectrum of biological activities. To access novel hybrids with pyrazole ring, in this work we synthesized twenty pyrazole-carboxylic acids and twenty pyrazole-carboxamides, using simple synthetic methods, to be used as building blocks in the development of new structures.
- Ferreira, Byanca Silva,Silva, Rafaela Corrêa,Souto, Bernardo Araújo,Dos Santos, Maurício Silva
-
p. 335 - 343
(2021/09/07)
-
- The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition
-
In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC50 > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
- Chen, Hui,Wang, Bin,Li, Peng,Yan, Hong,Li, Gang,Huang, Haihong,Lu, Yu
-
supporting information
(2021/03/26)
-
- Targeting Pim Kinases and DAPK3 to Control Hypertension
-
Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications. Carlson et al. use crystal structure-guided medicinal chemistry techniques to develop a dual Pim/DAPK3 inhibitor (HS56) that reduces myosin phosphorylation and contractility in smooth muscle. Their findings reveal the contribution of Pim kinases to the pathology of hypertension, suggesting a novel multi-target engagement strategy for molecularly targeted antihypertensive medications.
- Carlson, David A.,Singer, Miriam R.,Sutherland, Cindy,Redondo, Clara,Alexander, Leila T.,Hughes, Philip F.,Knapp, Stefan,Gurley, Susan B.,Sparks, Matthew A.,MacDonald, Justin A.,Haystead, Timothy A.J.
-
p. 1195 - 32,1207
(2018/07/06)
-
- DIAZOLE LACTAMS
-
Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are diazole lactam derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.
- -
-
Paragraph 0152; 0153
(2014/06/24)
-
- PYRAZOLO-PYRIDINONE DERIVATIVES AND METHODS OF USE
-
The present invention comprises a new class of compounds useful for the prophylaxis and treatment of pro-inflammatory cytokine mediated diseases, and in particular, p38 activity mediated inflammation and related conditions. The compounds have a general Fo
- -
-
Page/Page column 43
(2009/05/30)
-
- Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase
-
A novel class of fused pyrazole-derived inhibitors of p38α mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNF
- Wurz, Ryan P.,Pettus, Liping H.,Xu, Shimin,Henkle, Bradley,Sherman, Lisa,Plant, Matthew,Miner, Kent,McBride, Helen,Wong, Lu Min,Saris, Christiaan J.M.,Lee, Matthew R.,Chmait, Samer,Mohr, Christopher,Hsieh, Faye,Tasker, Andrew S.
-
scheme or table
p. 4724 - 4728
(2010/05/17)
-
