title: Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles.
abstract: The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50= 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC50= 6.7 μM), CRP-XL (IC50= 53.5 μM), and convulxin (CVX) (IC50= 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50= 10.4 μM; CRP-XL, IC50= 158 μM; CVX, IC50= 11 μM) than any of its enantiomers S (6c) (collagen, IC50= 25.3 μM; CRP-XL, IC50= 181.4 μM; CVX, IC50= 9 μM) and R (6d) (collagen, IC50= 126.3 μM; CRP-XL, IC50> 500 μM; CVX, IC50= 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.
authors.affiliation: Academy of Scientific and Innovative Research , New Delhi 110 025, India.
authors.forename: Shome S
authors.initials: SS
authors.lastname: Bhunia
authors.forename: Ankita
authors.initials: A
authors.lastname: Misra
authors.forename: Imran A
authors.initials: IA
authors.lastname: Khan
authors.forename: Stuti
authors.initials: S
authors.lastname: Gaur
authors.forename: Manish
authors.initials: M
authors.lastname: Jain
authors.forename: Surendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf , Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Aaruni
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf , Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hohlfield
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
authors.affiliation: Academy of Scientific and Innovative Research , New Delhi 110 025, India.
authors.forename: Anil K
authors.identifier: 0000-0002-0212-7246
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*
chemical_list: D000991:Antithrombins; D007211:Indoles; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI