890841-23-3Relevant articles and documents
The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors
Deaton, David N.,Do, Young,Holt, Jason,Jeune, Michael R.,Kramer, H. Fritz,Larkin, Andrew L.,Orband-Miller, Lisa A.,Peckham, Gregory E.,Poole, Chuck,Price, Daniel J.,Schaller, Lee T.,Shen, Ying,Shewchuk, Lisa M.,Stewart, Eugene L.,Stuart, J. Darren,Thomson, Stephen A.,Ward, Paris,Wilson, Joseph W.,Xu, Tianshun,Guss, Jeffrey H.,Musetti, Caterina,Rendina, Alan R.,Affleck, Karen,Anders, David,Hancock, Ashley P.,Hobbs, Heather,Hodgson, Simon T.,Hutchinson, Jonathan,Leveridge, Melanie V.,Nicholls, Harry,Smith, Ian E.D.,Somers, Don O.,Sneddon, Helen F.,Uddin, Sorif,Cleasby, Anne,Mortenson, Paul N.,Richardson, Caroline,Saxty, Gordon
, p. 1456 - 1478 (2019)
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials
Zhang, Yiqun,Clark, Julie A.,Connelly, Michele C.,Zhu, Fangyi,Min, Jaeki,Guiguemde, W. Armand,Pradhan, Anupam,Iyer, Lalitha,Furimsky, Anna,Gow, Jason,Parman, Toufan,El Mazouni, Farah,Phillips, Margaret A.,Kyle, Dennis E.,Mirsalis, Jon,Guy, R. Kiplin
, p. 4205 - 4219 (2012/07/02)
Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof
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Page/Page column 48, (2008/06/13)
Compounds that are antagonists of the VR1 receptor, having formula (I) [image] or a pharmaceutically acceptable salt, prodrug, or salt of a prodrug thereof, wherein A1, A2, A3, A4, R7, R8, R9, X, Y, Z, L, n, and m, are as defined herein, and are useful in disorders prevented or ameliorated by inhibiting the VR1 receptor.
