Identification of 4‑(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2)

LOXL2
catalyzes the oxidative deamination of ε-amines of
lysine and hydroxylysine residues within collagen and elastin, generating
reactive aldehydes (allysine). Condensation with other allysines or
lysines drives the formation of inter- and intramolecular cross-linkages,
a process critical for the remodeling of the ECM. Dysregulation of
this process can lead to fibrosis, and LOXL2 is known to be upregulated
in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic
activity represent a useful option for the treatment of fibrosis.
Herein, we describe optimization of an initial hit 2,
resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)­pyridin-2-yl)­oxy)­phenyl)­(3-fluoro-4-hydroxypyrrolidin-1-yl)­methanone 28, a potent irreversible inhibitor of LOXL2 that is highly
selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin
model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which
has progressed into healthy volunteer Phase 1 trials, making it the
“first-in-class” small-molecule LOXL2 inhibitor to enter
clinical development.