View source for 5l01


==Tryptophan 5-hydroxylase in complex with inhibitor (3~{S})-8-[2-azanyl-6-[(1~{R})-1-(4-chloranyl-2-phenyl-phenyl)-2,2,2-tris(fluoranyl)ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid==
<StructureSection load='5l01' size='340' side='right' caption='[[5l01]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5l01]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L01 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L01 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Z4:(3~{S})-8-[2-AZANYL-6-[(1~{R})-1-(4-CHLORANYL-2-PHENYL-PHENYL)-2,2,2-TRIS(FLUORANYL)ETHOXY]PYRIMIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECANE-3-CARBOXYLIC+ACID'>6Z4</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5j6d|5j6d]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tryptophan_5-monooxygenase Tryptophan 5-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.16.4 1.14.16.4] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5l01 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l01 OCA], [http://pdbe.org/5l01 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l01 RCSB], [http://www.ebi.ac.uk/pdbsum/5l01 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l01 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== 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<ref>PMID:28041831</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5l01" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Tryptophan 5-monooxygenase]]
[[Category: Goldberg, D R]]
[[Category: Holt, M C]]
[[Category: Lombaert, S De]]
[[Category: Stein, A J]]
[[Category: Acyl]]
[[Category: Iron]]
[[Category: Oxidoreductase-inhibitor complex]]
[[Category: Quanidine]]
[[Category: Tph1]]