189500-91-2Relevant academic research and scientific papers
A fluorescent target-guided Paal-Knorr reaction
Kornienko, Alexander,La Clair, James J.,Maslivetc, Vladimir,Wagh, Sachin B.
, p. 37035 - 37039 (2020/10/19)
It has become increasingly apparent that high-diversity chemical reactions play a significant role in the discovery of bioactive small molecules. Here, we describe an expanse of this paradigm, combining a ‘target-guided synthesis’ concept with Paal-Knorr chemistry applied to the preparation of fluorescent ligands for human prostaglandin-endoperoxide synthase (COX-2).
Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/ cyclooxygenase-1 selectivity
Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Supino, Sibilla,Forli, Stefano,Rovini, Michele,Cappelli, Andrea,Manetti, Fabrizio,Botta, Maurizio,Sautebin, Lidia,Rossi, Antonietta,Pergola, Carlo,Ghelardini, Carla,Vivoli, Elisa,Makovec, Francesco,Anzellotti, Paola,Patrignani, Paola,Anzini, Maurizio
, p. 5403 - 5411 (2008/03/14)
The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase- 2
Khanna, Ish K.,Weier, Richard M.,Yu, Yi,Collins, Paul W.,Miyashiro, Julie M.,Koboldt, Carol M.,Veenhuizen, Amy W.,Currie, Jerry L.,Seibert, Karen,Isakson, Peter C.
, p. 1619 - 1633 (2007/10/03)
Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = > 1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40- 80 nm) with excellent selectivity(1200 to >2500) vs COX-1, Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC50 = 30-120 nm). In vivo testing in the carrageenan- induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED50 of 4.7 mpk.
