3 research outputs found
Small Molecule Lysyl Oxidase-like 2 (LOXL2) Inhibitors: The Identification of an Inhibitor Selective for LOXL2 over LOX
Two series of novel
LOXL2 enzyme inhibitors are described: benzylamines
substituted with electron withdrawing groups at the <i>para</i>-position and 2-substituted pyridine-4-ylmethanamines. The most potent
compound, (2-chloropyridin-4-yl)Âmethanamine <b>20</b> (hLOXL2
IC<sub>50</sub> = 126 nM), was shown to be selective for LOXL2 over
LOX and three other amine oxidases (MAO-A, MAO-B, and SSAO). Compound <b>20</b> is the first published small molecule inhibitor selective
for LOXL2 over LOX
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
Identification of 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea Hydrochloride (CEP-32496), a Highly Potent and Orally Efficacious Inhibitor of V-RAF Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) V600E
The Ras/RAF/MEK/ERK mitogen-activated protein kinase
(MAPK) signaling
pathway plays a central role in the regulation of cell growth, differentiation,
and survival. Expression of mutant BRAF<sup>V600E</sup> results in
constitutive activation of the MAPK pathway, which can lead to uncontrolled
cellular growth. Herein, we describe an SAR optimization campaign
around a series of quinazoline derived BRAF<sup>V600E</sup> inhibitors.
In particular, the bioisosteric replacement of a metabolically sensitive <i>tert</i>-butyl group with fluorinated alkyl moieties is described.
This effort led directly to the identification of a clinical candidate,
compound <b>40</b> (CEP-32496). Compound <b>40</b> exhibits
high potency against several BRAF<sup>V600E</sup>-dependent cell lines
and selective cytotoxicity for tumor cell lines expressing mutant
BRAF<sup>V600E</sup> versus those containing wild-type BRAF. Compound <b>40</b> also exhibits an excellent PK profile across multiple preclinical
species. In addition, significant oral efficacy was observed in a
14-day BRAF<sup>V600E</sup>-dependent human Colo-205 tumor xenograft
mouse model, upon dosing at 30 and 100 mg/kg BID