Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening.
With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.
Carosati
Emanuele
E
Dipartimento di Chimica, Università degli Studi di Perugia, Via Elce di Sotto 10, 06123 Perugia, Italia.
Budriesi
Roberta
R
Ioan
Pierfranco
P
Ugenti
Maria P
MP
Frosini
Maria
M
Fusi
Fabio
F
Corda
Gaetano
G
Cosimelli
Barbara
B
Spinelli
Domenico
D
Chiarini
Alberto
A
Cruciani
Gabriele
G