posted on 2023-11-28, 15:40authored byGebhard Thoma, Christian Markert, Rainer Lueoend, Wolfgang Miltz, Carsten Spanka, Birgit Bollbuck, Romain M. Wolf, Honnappa Srinivas, Carlos A. Penno, Michael Kiffe, Monika Gajewska, Dallas Bednarczyk, Grazyna Wieczorek, Amanda Evans, Christian Beerli, Till A. Röhn
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.