8QOW

LTA4 hydrolase in complex with compound 2(S)

Summary for 8QOW

• Entry DOI: 10.2210/pdb8qow/pdb
• Related: 7AUZ
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, ACETATE ION, ... (7 entities in total)
• Functional Keywords: lta4h, inhibitors, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 70447.10

Authors

Srinivas, H. (deposition date: 2023-09-29, release date: 2023-12-06, Last modification date: 2023-12-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)