2 research outputs found
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)Âpyridin-2-yl)Âoxy)Âphenyl)Â(3-fluoro-4-hydroxypyrrolidin-1-yl)Âmethanone <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
Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate‑1 Receptor
APD334
was discovered as part of our internal effort to identify
potent, centrally available, functional antagonists of the S1P<sub>1</sub> receptor for use as next generation therapeutics for treating
multiple sclerosis (MS) and other autoimmune diseases. APD334 is a
potent functional antagonist of S1P<sub>1</sub> and has a favorable
PK/PD profile, producing robust lymphocyte lowering at relatively
low plasma concentrations in several preclinical species. This new
agent was efficacious in a mouse experimental autoimmune encephalomyelitis
(EAE) model of MS and a rat collagen induced arthritis (CIA) model
and was found to have appreciable central exposure