Bertrand Heckmann

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]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 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 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 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.

Balanced AT1 and AT2 angiotensin II antagonists. I. New orally active 5-carboxyl imidazolyl biphenyl sulfonylureas

Abstract A series of substituted imidazolyl biphenyl sulfonylureas have been synthesized. Substitution on the imidazole ring but essentially on the urea side chain significantly increased AT2 binding with cyclohexylmethyl, cyclopentylmethyl and benzyl as the most effective substituents. Imidazole 13d, as a representative member of this series, displayed nanomolar binding affinity for both the AT1 and AT2 angiotensin II receptor subtypes as well as oral activity.

Balanced AT1 and AT2 angiotensin II antagonists. III. potent and orally active 5-β-ketosulfoxide imidazolyl biphenyl sulfonylureas

Abstract In the imidazolyl biphenyl sulfonylurea series, effects of substitution in position 5 of the imidazole ring with enolic ketone moiety were studied on AT 2 binding. β-ketosulfoxide, β-ketosulfone and β-ketoester proved to be highly effective substituents for potent nanomolar binding affinity on both AT 1 and AT 2 receptor subtypes. This led to the identification of β-ketophenylsulfoxide RU 64276 as a potent and orally active AT 1 antagonist and AT 2 binding inhibitor.

Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]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-a]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 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

Balanced AT1 and AT2 angiotensin II antagonists. II. Potent 5 α-hydroxyacid imidazolyl biphenyl sulfonylureas

Abstract Introduction of an α-hydroxyacid moiety in position 5 of the imidazole ring within the imidazolyl biphenyl sulfonyl urea series significantly increased AT2 binding. Structure activity relationship around this moiety is described and gave rise to balanced AII inhibitors with nanomolar affinity on both AT1 and AT2 receptors and with an AT 2 AT 1 ratio of between 0.4 and 3.