6n69 | pdb_00006n69
rat hPGDS complexed with a quinoline
Structural highlights
Function[HPGDS_RAT] Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.[1] [2] [3] [4] Publication Abstract from PubMedWith 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=220,000nM, 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=3,100nM, 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=9.9nM, 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. The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.,Deaton DN, Do Y, Holt J, Jeune MR, Kramer HF, Larkin AL, Orband-Miller LA, Peckham GE, Poole C, Price DJ, Schaller LT, Shen Y, Shewchuk LM, Stewart EL, Stuart JD, Thomson SA, Ward P, Wilson JW, Xu T, Guss JH, Musetti C, Rendina AR, Affleck K, Anders D, Hancock AP, Hobbs H, Hodgson ST, Hutchinson J, Leveridge MV, Nicholls H, Smith IED, Somers DO, Sneddon HF, Uddin S, Cleasby A, Mortenson PN, Richardson C, Saxty G Bioorg Med Chem. 2019 Apr 15;27(8):1456-1478. doi: 10.1016/j.bmc.2019.02.017., Epub 2019 Feb 11. PMID:30858025[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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