2. Academic Validation
  3. Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase

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

  • J Med Chem. 2023 Dec 14;66(23):16410-16425. doi: 10.1021/acs.jmedchem.3c01866.
Gebhard Thoma 1,  Christian Markert 1,  Rainer Lueoend 1,  Wolfgang Miltz 1,  Carsten Spanka 1,  Birgit Bollbuck 1,  Romain M Wolf 1,  Honnappa Srinivas 2,  Carlos A Penno 2,  Michael Kiffe 3,  Monika Gajewska 3,  Dallas Bednarczyk 4,  Grazyna Wieczorek 5,  Amanda Evans 5,  Christian Beerli 5,  Till A Röhn 5
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
  • 2 Chemical Biology & Therapeutics, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
  • 3 PK Sciences, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
  • 4 Discovery & Translational Lab, Biomedical Research, Novartis Pharma AG, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 5 Immunology Disease Area, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
PMID: 38015154 DOI: 10.1021/acs.jmedchem.3c01866
Abstract

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.

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