15001-08-8Relevant academic research and scientific papers
Synthesis of pyrazole-carboxamides and pyrazole-carboxylic acids derivatives: Simple methods to access powerful building blocks
Ferreira, Byanca Silva,Silva, Rafaela Corrêa,Souto, Bernardo Araújo,Dos Santos, Maurício Silva
, p. 335 - 343 (2021/09/07)
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.
Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups
Corte, James R.,Pinto, Donald J. P.,Fang, Tianan,Osuna, Honey,Yang, Wu,Wang, Yufeng,Lai, Amy,Clark, Charles G.,Sun, Jung-Hui,Rampulla, Richard,Mathur, Arvind,Kaspady, Mahammed,Neithnadka, Premsai Rai,Li, Yi-Xin Cindy,Rossi, Karen A.,Myers, Joseph E.,Sheriff, Steven,Lou, Zhen,Harper, Timothy W.,Huang, Christine,Zheng, Joanna J.,Bozarth, Jeffrey M.,Wu, Yiming,Wong, Pancras C.,Crain, Earl J.,Seiffert, Dietmar A.,Luettgen, Joseph M.,Lam, Patrick Y. S.,Wexler, Ruth R.,Ewing, William R.
supporting information, p. 784 - 803 (2020/02/04)
Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.
Targeting Pim Kinases and DAPK3 to Control Hypertension
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)
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.
Synthesis of 3H-pyrazolo[3,4-c]isoquinolines and thieno[3,2-c]isoquinolines via cascade imination/intramolecular decarboxylative coupling
Pandey, Garima,Bhowmik, Subhendu,Batra, Sanjay
supporting information, p. 5044 - 5047 (2013/10/22)
A general approach for the synthesis of 3H-pyrazolo[3,4-c]isoquinolines and thieno[3,2-c]isoquinolines is described involving the implementation of a cascade imination/intramolecular decarboxylative coupling between potassium 2-amino(hetero)benzoates and 2-haloarylaldehydes. The reactions of pyrazole-based substrates require a Pd-Cu bimetallic system for superior yields whereas the thienyl-based substrates afford the products in excellent yields with a Pd-catalyst only.
NOVEL MACROCYCLES AS FACTOR XIA INHIBITORS
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Paragraph 00321, (2013/03/26)
The present invention provides compounds of Formula (Ia): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
4-carboxy-1-phenyl-5-pyrazolecarboxamides in the production of hybrid cereal grain seed
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, (2008/06/13)
Pollen formation in cereal grain plants is inhibited by application of a 4-carboxy(or derivative)-1-aryl-5-pyrazolecarboxamide. Production of hybrid seed is facilitated by use of the compounds.
Pollen formation inhibiting 1-phenyl-4-carboxy-5-pyrazolecarboxamides
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, (2008/06/13)
Pollen formation in cereal grain plants is inhibited by application of a 4-carboxy(or derivative)-1-aryl-5-pyrazolecarboxamide. Production of hybrid seed is facilitated by use of the compounds.
Herbicidal and algicidal 1,5-disubstituted-1H-pyrazole-4-carboxamides
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, (2008/06/13)
1,5-Disubstituted-1H-pyrazole-4-carboxamide derivatives, useful as herbicides and aquatic algicides.
