- Discovery of Novel Pyrazolo[3,4- b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension
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Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.
- Hu, Liqing,Li, Lijun,Chang, Qi,Fu, Songsen,Qin, Jia,Chen, Zhuo,Li, Xiaohui,Liu, Qinglian,Hu, Gaoyun,Li, Qianbin
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- Preparation of novel azidopyrazole derivatives with anticipated cytotoxic and antimicrobial activities
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The reactions of azidopyrazole with some of primary amines and active methylene compounds were studied. Structures of the prepared compounds were identified using spectroscopic techniques. The reactions mechanisms were also proposed. The cytotoxic and antimicrobial activities were also examined for the newly synthesized compounds.
- Chen, Yu-Cheng,El-Hussieny, Marwa,El-Sayed, Naglaa F.,El-Shazly, Mohamed,Ewies, Ewies F.,Liu, Yi-Chang
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- Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity
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A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl- β-d-ribose-2′-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.
- Panda, Manoranjan,Ramachandran, Sreekanth,Ramachandran, Vasanthi,Shirude, Pravin S.,Humnabadkar, Vaishali,Nagalapur, Kavitha,Sharma, Sreevalli,Kaur, Parvinder,Guptha, Supreeth,Narayan, Ashwini,Mahadevaswamy, Jyothi,Ambady, Anisha,Hegde, Naina,Rudrapatna, Suresh S.,Hosagrahara, Vinayak P.,Sambandamurthy, Vasan K.,Raichurkar, Anandkumar
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p. 4761 - 4771
(2014/07/07)
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- Synthesis, characterisation and antimicrobial activity of 3-methyl-6-(aryl)-1-phenyl-1Hpyrazolo[ 3,4-b]pyridine
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A series of 3-methyl-6-(aryl)-1-phenyl-1H-pyrazolo[3,4- b]pyridine have been synthesized in one step by treating 5-azido- 3-methyl-1-phenyl-1H-pyrazol- 4-carboxaldehyde with suitably substituted acetophenones in basic medium. This reaction is a good examp
- Girisha,Kalluraya, Balakrishna,Vidyashree Jois
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p. 1767 - 1770
(2013/02/23)
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- Synthesis and antibacterial activity of some novel pyrazolopyridine derivatives
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Eight pyrazolo[3,4-b]pyridine derivatives have been synthesized by Friedlaender condensation of 5-aminopyrazole-4-carbaldehyde with active methylene compounds in basic medium. These compounds have been screened for their antibacterial activity against two Gram-negative and two Gram-positive bacterium. Pyrazolopyridines having the carboxamide group at the 5-position showed moderate to good activity against P. aeruginosa, E. coli, S. pneumoniae, and B. cereus.
- Panda,Karmakar,Jena
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p. 1500 - 1508
(2012/01/05)
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- Design, synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: A new class of potent and selective acetylcholinesterase inhibitors
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A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo-[4,3-d]pyridine or pyrazolo[3,4-b] [1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brai
- Barreiro, Eliezer J.,Camara, Celso A.,Verli, Hugo,Brazil-Más, Leonora,Castro, Newton G.,Cintra, Wagner M.,Aracava, Yasco,Rodrigues, Carlos R.,Fraga, Carlos A. M.
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p. 1144 - 1152
(2007/10/03)
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- A facile synthesis of pyrazolo[3,4-b]pyridines
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Pyrazolo[3,4-b]pyridines (4) and (5) have been obtained by the condensation of 3-(alkyl/aryl)-5-amino-1-phenyl-1H-pyrazole-4-carboxaldehydes (3) with active methylene compounds viz: diethyl malonate and malononitrile.
- Ahluwalia,Goyal, Bindu
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p. 1341 - 1348
(2007/10/03)
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- Fused Pyrimidines by a Tandem Aza-Wittig / Electrocyclic Ring Closure Strategy: Synthesis of Pyrazolo pyrimidyne, Triazolo pyrimidyne, and Thiazolo pyrimidyne Derivatives
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The aza-Wittig reaction of iminophosphoranes derived from 5-azido -4-formylazoles or 4-azido-5-formylazoles with heterocumulenes leads to functionalized fused pyrimidines.Iminophosphoranes 12, derived from 5-azido-4-formylpyrazole, react under mild condit
- Molina, Pedro,Arques, Antonio,Vinader, Maria Victoria
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p. 4654 - 4662
(2007/10/02)
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- TANDEM AZA-WITTIG REACTION/ELECTROCYCLIC RING-CLOSURE A FACILE ENTRY TO THE SYNTHESIS OF FUSED PYRIMIDINES: PREPARATION OF PYRAZOLO AND 1,2,3-TRIAZOLOPYRIMIDINE DERIVATIVES.
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The aza-Wittig reaction of iminophosphoranes derived from 5-azido-4-formyl azoles, with isocyanates or carbon disulfide, leads to functionalized fused pyrimidines.
- Molina, Pedro,Arques, Antonio,Vinader, Victoria,Becher, Jan,Brondum, Klaus
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p. 4451 - 4454
(2007/10/02)
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