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 acidTryptophan 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

Structural highlights

5l01 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TPH1_HUMAN

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Holt M, Valentine J, Zavadoski W. Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2016.12.053

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OCA

[1] Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Holt M, Valentine J, Zavadoski W. Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2016.12.053

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