Synthesis and activity of N-benzyl pseudopeptides HIV protease inhibitors.
A series of N-benzyl pseudopeptides was designed, synthesized and tested as HIV-1 protease inhibitors. The ability of the new compounds containing N-benzyl hydroxyalkylamino acid core structure to inhibit HIV replication in cell culture is comparable to their capacity to inhibit the isolated enzyme, a result compatible with good pharmacokinetic properties of these derivatives. The pseudotripeptide Fmoc-Leu-N(Bzl)Hse-Met-NH-tBu was the best inhibitor of the series (IC(50)=170 nM) showing promising inhibition of viral replication (ED(50)=52 nM). All new compounds exhibit high enzymatic resistance and stability against cell cultures and plasma enzymes.
Marastoni
Mauro
M
Dipartimento di Scienze Farmaceutiche e Centro di Biotecnologie, via Fossato di Mortara 17-19, Università di Ferrara, I-44100, Ferrara, Italy. mrn@dns.unife.it
Bazzaro
Martina
M
Bortolotti
Fabrizio
F
Tomatis
Roberto
R
D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D001593:Benzyl Compounds; D017320:HIV Protease Inhibitors; D010455:Peptides; D016333:HIV Protease