1288977-98-9Relevant academic research and scientific papers
Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis
Brebion, Franck,Gosmini, Romain,Deprez, Pierre,Varin, Marie,Peixoto, Christophe,Alvey, Luke,Jary, Hélène,Bienvenu, Natacha,Triballeau, Nicolas,Blanque, Roland,Cottereaux, Céline,Christophe, Thierry,Vandervoort, Nele,Mollat, Patrick,Touitou, Robert,Leonard, Philip,De Ceuninck, Frédéric,Botez, Iuliana,Monjardet, Alain,Van Der Aar, Ellen,Amantini, David
supporting information, p. 2937 - 2952 (2021/04/12)
There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochemical activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC50 1.5 μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618).
Discovery of (1 S,2 R,3 R)-2,3-dimethyl-2-phenyl-1- sulfamidocyclopropanecarboxylates: Novel and highly selective aggrecanase inhibitors
Shiozaki, Makoto,Maeda, Katsuya,Miura, Tomoya,Kotoku, Masayuki,Yamasaki, Takayuki,Matsuda, Isamu,Aoki, Kenta,Yasue, Katsutaka,Imai, Hiroto,Ubukata, Minoru,Suma, Akira,Yokota, Masahiro,Hotta, Takahiro,Tanaka, Masahiro,Hase, Yasunori,Haas, Julia,Fryer, Andrew M.,Laird, Ellen R.,Littmann, Nicole M.,Andrews, Steven W.,Josey, John A.,Mimura, Takayuki,Shinozaki, Yuichi,Yoshiuchi, Hiromi,Inaba, Takashi
experimental part, p. 2839 - 2863 (2011/06/24)
Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1′ groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1′ groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1′ portion of 1,2,3,4-tetrahydropyrido[3′,4′:4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.
