Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase

被引：3

作者：

Thoma, Gebhard ^{[1
]}

Markert, Christian ^{[1
]}

Lueoend, Rainer ^{[1
]}

Miltz, Wolfgang ^{[1
]}

Spanka, Carsten ^{[1
]}

Bollbuck, Birgit ^{[1
]}

Wolf, Romain M. ^{[1
]}

Srinivas, Honnappa ^{[2
]}

Penno, Carlos A. ^{[2
]}

Kiffe, Michael ^{[3
]}

Gajewska, Monika ^{[3
]}

Bednarczyk, Dallas ^{[4
]}

Wieczorek, Grazyna ^{[5
]}

Evans, Amanda ^{[5
]}

Beerli, Christian ^{[5
]}

Rohn, Till A. ^{[5
]}

机构：

[1] Global Discovery Chem, Biomed Res, Novartis Pharm AG, CH-4002 Basel, Switzerland

[2] Novartis Pharm AG, Chem Biol & Therapeut, Biomed Res, CH-4002 Basel, Switzerland

[3] PK Sci Biomed Res, Novartis Pharm AG, CH-4002 Basel, Switzerland

[4] Discovery & Translat Lab, Biomed Res, Novartis Pharm AG, Cambridge, MA 02139 USA

[5] Immunol Dis Area, Biomed Res, Novartis Pharm AG, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 23期

关键词：

DISEASE; FTY720; ASSAY; BIOLOGY; BINDING; LYS006;

D O I：

10.1021/acs.jmedchem.3c01866

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 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 O-phosphorylation of the (R)-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the (S)-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound (S)-2 with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound (S)-2 showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound (S)-2 has the potential for a low oral efficacious dose administered once daily.

引用

页码：16410 / 16425

页数：16

共 41 条

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JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (22) : 13973 - 13993

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