5-chloro-3-(phenylsulfonyl)indole-2-carboxamide: a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase.
A series of highly potent, structurally novel, non-nucleoside RT inhibitors has been described. Low nanomolar concentrations of 5-chloro-3-(phenylsulfonyl)-indole-2-carboxamide (1) inhibit the HIV-1 RT enzyme in vitro and HTLVIIIb viral spread in MT-4 human T-lymphoid cells. Good oral bioavailability was observed in rhesus monkeys upon oral dosing of 1 as a suspension in methocel. When compared to other non-nucleoside inhibitors (e.g. 15-18), 1 possesses improved inhibitory potency with respect to the wild-type RT, as well as the K103N and Y181C mutant enzymes. Additional studies within this class of inhibitors are in progress.
Williams
T M
TM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486-0004.
Ciccarone
T M
TM
MacTough
S C
SC
Rooney
C S
CS
Balani
S K
SK
Condra
J H
JH
Emini
E A
EA
Goldman
M E
ME
Greenlee
W J
WJ
Kauffman
L R
LR
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001682:Biological Availability; D006678:HIV / Q000187:drug effects; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors; D013454:Sulfoxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C081119:5-chloro-3-(phenylsulfonyl)indole-2-carboxamide; D000998:Antiviral Agents; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; D013454:Sulfoxides; D054303:HIV Reverse Transcriptase