805960-27-4Relevant 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).
BENZAZEPINE DICARBOXAMIDE COMPOUNDS WITH TERTIARY AMIDE FUNCTION
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Page/Page column 39; 47, (2017/12/29)
This invention relates to new benzazepine dicarboxamide compounds of the formula (I) wherein R1 to R 3 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one
Ablordeppey, Seth Y.,Altundas, Ramazan,Bricker, Barbara,Zhu, Xue Y.,Suresh Kumar, Eyunni V.K.,Jackson, Tanise,Khan, Abdul,Roth, Bryan L.
, p. 7291 - 7301 (2008/12/23)
The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED50 value.
Diazabicyclooctane derivatives and therapeutic uses thereof
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, (2008/06/13)
The present invention provides diazabicyclooctane derivatives of formula (I): and pharmaceutically acceptable salts thereof, wherein the group represents R1 and R2 are selected independently from H, (C1-C6)alkyl
