Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators

A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-<i>N</i>-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)­imidazolidin-1-yl]-2-(trifluoromethyl)­benzonitrile ((+)-<b>11b</b>) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (<i>A</i>₅₀ = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-<b>11b</b>, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar

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, 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