1. 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).
- Author
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Rowbottom MW, Bain G, Calderon I, Lasof T, Lonergan D, Lai A, Huang F, Darlington J, Prodanovich P, Santini AM, King CD, Goulet L, Shannon KE, Ma GL, Nguyen K, MacKenna DA, Evans JF, and Hutchinson JH
- Subjects
- Administration, Oral, Amino Acid Oxidoreductases metabolism, Animals, Disease Models, Animal, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors therapeutic use, Fibrosis, Halogenation, Humans, Lung drug effects, Lung enzymology, Lung pathology, Lung Diseases drug therapy, Lung Diseases enzymology, Lung Diseases pathology, Male, Methylation, Mice, Inbred C57BL, Models, Molecular, Pyridines administration & dosage, Pyridines therapeutic use, Structure-Activity Relationship, Amino Acid Oxidoreductases antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Pyridines chemistry, Pyridines pharmacology
- Abstract
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.
- Published
- 2017
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