Structure-activity and structure-metabolism relationships of HIV protease inhibitors containing the 3-hydroxy-2-methylbenzoyl-allophenylnorstatine structure
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Updated: Aug 29, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Tsutomu Mimoto1, Keisuke Terashima, Satoshi Nojima
1Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98, Kasugade Naka 3-Chome, Konohanaku, Osaka, 554-0022, Japan. tmimoto@sumitomopharm.co.jp
Abstract:
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.
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