Design and synthesis of several small-size HTLV-I protease inhibitors with different hydrophilicity profiles

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• 作者：Jeffrey-Tri Nguyen^a ; Keiko Kato^a ; Koushi Hidaka^a ; Henri-Obadja Kumada^a ; Tooru Kimura^a ; Yoshiaki Kiso ; ^a ; ^{kiso@mb.kyoto-phu.ac.jp}
• 关键词：Human T cell lymphotropic virus ; HAM/TSP ; Adult T cell leukemia ; Aspartic protease ; Inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 April 2011
• 年：2011
• 卷：21
• 期：8
• 页码：2425-2429
• 全文大小：536 K

文摘

The human T cell leukemia/lymphotropic virus type 1 (HTLV-I) is clinically associated with adult T cell leukemia/lymphoma, HTLV-I associated myelopathy/tropical spastic paraparesis, and a number of other chronic inflammatory diseases. To stop the replication of the virus, we developed highly potent tetrapeptidic HTLV-I protease inhibitors. In a recent X-ray crystallography study, several of our inhibitors could not form co-crystal complexes with the protease due to their high hydrophobicity. In the current study, we designed, synthesized and evaluated the HTLV-I protease inhibition potency of compounds with hydrophilic end-capping moieties with the aim of improving pharmaceutic and pharmacokinetic properties.