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

5L01 の概要

• エントリーDOI: 10.2210/pdb5l01/pdb
• 関連するPDBエントリー: 5J6D
• 分子名称: Tryptophan 5-hydroxylase 1, FE (III) ION, (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, ... (4 entities in total)
• 機能のキーワード: tph1, iron, acyl, quanidine, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51678.94

構造登録者

Stein, A.J.,Goldberg, D.R.,De Lombaert, S.,Holt, M.C. (登録日: 2016-07-26, 公開日: 2017-01-25, 最終更新日: 2023-10-04)

主引用文献

Goldberg, D.R.,De Lombaert, S.,Aiello, R.,Bourassa, P.,Barucci, N.,Zhang, Q.,Paralkar, V.,Stein, A.J.,Holt, M.,Valentine, J.,Zavadoski, W.
Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.
Bioorg. Med. Chem. Lett., 27:413-419, 2017

PubMed Abstract: 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.

PubMed: 28041831
DOI: 10.1016/j.bmcl.2016.12.053

実験手法

X-RAY DIFFRACTION (1.9 Å)