8QQ4

LTA4 hydrolase in complex with compound 6(R)

8QQ4 の概要

• エントリーDOI: 10.2210/pdb8qq4/pdb
• 分子名称: Leukotriene A-4 hydrolase, ZINC ION, ACETATE ION, ... (7 entities in total)
• 機能のキーワード: lta4h, inhibitors, hydrolase
• 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: 70590.50

構造登録者

Srinivas, H. (登録日: 2023-10-03, 公開日: 2023-12-06, 最終更新日: 2023-12-27)

主引用文献

Thoma, G.,Markert, C.,Lueoend, R.,Miltz, W.,Spanka, C.,Bollbuck, B.,Wolf, R.M.,Srinivas, H.,Penno, C.A.,Kiffe, M.,Gajewska, M.,Bednarczyk, D.,Wieczorek, G.,Evans, A.,Beerli, C.,Rohn, T.A.
Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase.
J.Med.Chem., 66:16410-16425, 2023

PubMed Abstract: The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective -phosphorylation of the ()-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the ()-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound ()- with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound ()- showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound ()- has the potential for a low oral efficacious dose administered once daily.

PubMed: 38015154
DOI: 10.1021/acs.jmedchem.3c01866

実験手法

X-RAY DIFFRACTION (1.6 Å)