Structure-activity and structure-metabolism relationships of HIV protease inhibitors containing the 3-hydroxy-2-methylbenzoyl-allophenylnorstatine structure.
A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted all-phenylnorstatine [APNS: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were designed and synthesized. From the structure-metabolism relationship of this type of HIV protease inhibitors, the compounds having para substitution of the phenyl ring of Apns and/or 2,6-disubstitution of the P2' benzylamine were found to be able to avoid the P2 phenol glucuronidation that occurs with SM-319777 (formerly named JE-2147, KNI-764); one of the main metabolic pathways of SM-319777. These new analogues, such as SM-322377, had more desirable pharmacokinetic profiles and more potent antiviral activity against not only wild type HIV-1 but also the multi-drug-resistant HIV-1 than SM-319777.
Mimoto
Tsutomu
T
Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98, Kasugade Naka 3-Chome, Konohanaku, Osaka, 554-0022, Japan. tmimoto@sumitomopharm.co.jp
Terashima
Keisuke
K
Nojima
Satoshi
S
Takaku
Haruo
H
Nakayama
Mitsunobu
M
Shintani
Makoto
M
Yamaoka
Takashi
T
Hayashi
Hideya
H
D000818:Animals; D004285:Dogs; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010654:Phenylbutyrates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D019438:Ritonavir