The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase.
To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibitors, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found to inhibit HIV-1 RT. Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing favorable pharmacokinetic properties.
Ahgren
C
C
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Backro
K
K
Bell
F W
FW
Cantrell
A S
AS
Clemens
M
M
Colacino
J M
JM
Deeter
J B
JB
Engelhardt
J A
JA
Hogberg
M
M
Jaskunas
S R
SR
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D001569:Benzodiazepines / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007364:Intercalating Agents / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
D000998:Antiviral Agents; D007093:Imidazoles; D007364:Intercalating Agents; C095795:LY 73497; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D014230:Triazoles; D001569:Benzodiazepines; C067413:R-82913; C062942:2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole; D004259:DNA-Directed DNA Polymerase; D013890:Thiourea; C095511:trovirdine