- Acid Derivatives of Pyrazolo[1,5-a]pyrimidine as Aldose Reductase Differential Inhibitors
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Aldose reductase (AKR1B1), the key enzyme of the polyol pathway, plays a crucial role in the development of long-term complications affecting diabetic patients. Nevertheless, the expedience of inhibiting this enzyme to treat diabetic complications has fai
- Quattrini, Luca,Coviello, Vito,Sartini, Stefania,Da Settimo, Federico,La Motta, Concettina,Balestri, Francesco,Cappiello, Mario,Moschini, Roberta,Del Corso, Antonella,Mura, Umberto
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- Novel Hinge-Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure-Activity Relationship Study on Tofacitinib Bioisosteres
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The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
- Gehringer, Matthias,Forster, Michael,Pfaffenrot, Ellen,Bauer, Silke M.,Laufer, Stefan A.
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supporting information
p. 2516 - 2527
(2015/08/24)
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- MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof of formula (I), including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention
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Page/Page column 50; 50-51
(2009/07/17)
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- Synthesis of pyrazolo[1,5-α]pyrimidinone regioisomers
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(Chemical Equation Presented) This work describes two distinct routes to prepare pyrazolo-[1,5-α]pyrimidin-7-ones and two distinct routes to prepare pyrazolo[1,5-α]pyrimidin-5-ones. Use of 1,3-dimethyluracil as the electrophile in the preparation of the p
- Gavrin, Lori K.,Lee, Arthur,Provencher, Brian A.,Massefski, Walter W.,Huhn, Stephen D.,Ciszewski, Gregory M.,Cole, Derek C.,McKew, John C.
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p. 1043 - 1046
(2008/02/04)
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