5tpg | pdb_00005tpg

Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors

spinqualitylabelsall models 5tpg, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tpg is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 7H5, CCN, FE, TRS Related: 5l01 Gene: TPH1, TPH, TPRH, TRPH (HUMAN) Activity: Tryptophan 5-monooxygenase, with EC number 1.14.16.4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system. Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.,Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Holt M, Valentine J, Zavadoski W Bioorg Med Chem Lett. 2017 Feb 1;27(3):413-419. doi: 10.1016/j.bmcl.2016.12.053. , Epub 2016 Dec 23. PMID:28041831 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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