3-Hydroxy-1,5-dihydro-pyrrol-2-one derivatives as advanced inhibitors of HIV integrase.
The two-metal binding model we previously reported as an inhibition mechanism of HIV integrase (HIV IN) produced a new direction in modification of 2-hydroxy-3-heteroaryl acrylic acid inhibitors (HHAAs). Here we present a novel series of HIV IN inhibitors having a 3-hydroxy-1,5-dihydro-pyrrol-2-one moiety (HDPO) as an advanced analog of HHAAs. This cyclic modification of the chelating region of HHAA produces a favorable configuration to coordinate two-metal ions in HIV IN, which consequently gave improvements in not only enzymatic assay but also antiviral cell based assay in many cases.
Kawasuji
Takashi
T
Shionogi Research Laboratories, Shionogi & Company, Ltd, Sagisu, Fukushima-ku, Osaka 553-0002, Japan. kawasuji@shionogi.co.jp
Fuji
Masahiro
M
Yoshinaga
Tomokazu
T
Sato
Akihiko
A
Fujiwara
Tamio
T
Kiyama
Ryuichi
R
D000577:Amides / Q000737:chemistry; D006678:HIV / Q000187:drug effects; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C522703:3-hydroxy-1,5-dihydro-pyrrol-2-one; D000577:Amides; D019428:HIV Integrase Inhibitors; D011758:Pyrroles; D019427:HIV Integrase; D009584:Nitrogen