6 research outputs found
Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a unique GPR84 negative allosteric modulator undergoing evaluation in a phase II clinical trial
GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5′-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein
Correction to Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2- a
Discovery of 2‑[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2‑<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis
Autotaxin is a circulating
enzyme with a major role in the production
of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA
axis has been suggested in many disease areas including pulmonary
fibrosis. Structural modifications of the known autotaxin inhibitor
lead compound <b>1</b>, to attenuate hERG inhibition, remove
CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties,
led to the identification of clinical candidate GLPG1690 (<b>11</b>). Compound <b>11</b> was able to cause a sustained reduction
of LPA levels in plasma in vivo and was shown
to be efficacious in a bleomycin-induced pulmonary fibrosis model
in mice and in reducing extracellular matrix deposition in the lung
while also reducing LPA 18:2 content in bronchoalveolar lavage fluid.
Compound <b>11</b> is currently being evaluated in an exploratory
phase 2a study in idiopathic pulmonary fibrosis patients
Discovery of 2‑[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2‑<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis
Autotaxin is a circulating
enzyme with a major role in the production
of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA
axis has been suggested in many disease areas including pulmonary
fibrosis. Structural modifications of the known autotaxin inhibitor
lead compound <b>1</b>, to attenuate hERG inhibition, remove
CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties,
led to the identification of clinical candidate GLPG1690 (<b>11</b>). Compound <b>11</b> was able to cause a sustained reduction
of LPA levels in plasma in vivo and was shown
to be efficacious in a bleomycin-induced pulmonary fibrosis model
in mice and in reducing extracellular matrix deposition in the lung
while also reducing LPA 18:2 content in bronchoalveolar lavage fluid.
Compound <b>11</b> is currently being evaluated in an exploratory
phase 2a study in idiopathic pulmonary fibrosis patients
Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic
FFA2,
also called GPR43, is a G-protein coupled receptor for short chain
fatty acids which is involved in the mediation of inflammatory responses.
A class of azetidines was developed as potent FFA2 antagonists. Multiparametric
optimization of early hits with moderate potency and suboptimal ADME
properties led to the identification of several compounds with nanomolar
potency on the receptor combined with excellent pharmacokinetic (PK)
parameters. The most advanced compound, 4-[[(<i>R</i>)-1-(benzo[<i>b</i>]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric
acid <b>99</b> (GLPG0974), is able to inhibit acetate-induced
neutrophil migration strongly in vitro and demonstrated ability to
inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific
epitope [AE], in a human whole blood assay. All together, these data
supported the progression of <b>99</b> toward next phases, becoming
the first FFA2 antagonist to reach the clinic
Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2‑<i>a</i>]pyridine Series of Autotaxin Inhibitors
Autotaxin
(ATX) is a secreted enzyme playing a major role in the
production of lysophosphatidic acid (LPA) in blood through hydrolysis
of lysophosphatidyl choline (LPC). The ATX–LPA signaling axis
arouses a high interest in the drug discovery industry as it has been
implicated in several diseases including cancer, fibrotic diseases,
and inflammation, among others. An imidazo[1,2-<i>a</i>]pyridine
series of ATX inhibitors was identified out of a high-throughput screening
(HTS). A cocrystal structure with one of these compounds and ATX revealed
a novel binding mode with occupancy of the hydrophobic pocket and
channel of ATX but no interaction with zinc ions of the catalytic
site. Exploration of the structure–activity relationship led
to compounds displaying high activity in biochemical and plasma assays,
exemplified by compound <b>40</b>. Compound <b>40</b> was
also able to decrease the plasma LPA levels upon oral administration
to rats