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 <b>2</b>, resulting in identification of racemic-<i>trans</i>-(3-((4-(aminomethyl)-6-(trifluoromethyl)­pyridin-2-yl)­oxy)­phenyl)­(3-fluoro-4-hydroxypyrrolidin-1-yl)­methanone <b>28</b>, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of <b>28</b> significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (<i>R</i>,<i>R</i>)-enantiomer <b>43</b> (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