189500-90-1Relevant articles and documents
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).
A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity
Battilocchio, Claudio,Poce, Giovanna,Alfonso, Salvatore,Porretta, Giulio Cesare,Consalvi, Sara,Sautebin, Lidia,Pace, Simona,Rossi, Antonietta,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Schenone, Silvia,Giordani, Antonio,Di Francesco, Luigia,Patrignani, Paola,Biava, Mariangela
, p. 3695 - 3701 (2013/07/25)
We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules.
Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme
Biava, Mariangela,Battilocchio, Claudio,Poce, Giovanna,Alfonso, Salvatore,Consalvi, Sara,Porretta, Giulio Cesare,Schenone, Silvia,Calderone, Vincenzo,Martelli, Alma,Testai, Lara,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Sautebin, Lidia,Rossi, Antonietta,Giordani, Antonio,Patrignani, Paola,Anzini, Maurizio
, p. 287 - 298 (2013/02/23)
The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds.
Novel analgesic/anti-inflammatory agents: Diarylpyrrole acetic esters endowed with nitric oxide releasing properties
Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Battilocchio, Claudio,Alfonso, Salvatore,Rovini, Michele,Valenti, Salvatore,Giorgi, Gianluca,Calderone, Vincenzo,Martelli, Alma,Testai, Lara,Sautebin, Lidia,Rossi, Antonietta,Papa, Giuseppina,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Giordani, Antonio,Anzellotti, Paola,Bruno, Annalisa,Patrignani, Paola,Anzini, Maurizio
experimental part, p. 7759 - 7771 (2012/01/03)
The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of 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.
SUBSTITUTED PYRROLYL COMPOUNDS FOR THE TREATMENT OF INFLAMMATION
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Page/Page column 9, (2008/06/13)
A class of pyrrolyl derivatives is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I wherein R1, R2, R3 and R4 are as described in the specification.
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.
