Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety

被引：2

作者：

Adachi, Kaoru ^{[1
]}

Manabe, Tomoyuki ^{[2
]}

Yamasaki, Takayuki ^{[3
]}

Suma, Akira ^{[2
]}

Orita, Takuya ^{[1
]}

Furuzono, Tomoko ^{[1
]}

Adachi, Tsuyoshi ^{[1
]}

Ohata, Yoshitsugu ^{[4
]}

Akiyama, Yoshiyuki ^{[5
]}

Miyazaki, Susumu ^{[1
]}

机构：

[1] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Chem Res Labs, 1-1,Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[2] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Innovat Implementat Labs, 1-1,Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[3] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Dept Res Planning, Preclin, 1-1,Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[4] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Biol Pharmacol Res Labs, 1-1,Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[5] Japan Tobacco Inc, Cent Pharmaceut Res Inst, DMPK Res Labs, 1-1,Murasaki Cho, Takatsuki, Osaka 5691125, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 110卷

关键词：

HIV-1; integrase; Allosteric inhibitor; LEDGF/p75; LEDGF/P75; MULTIMERIZATION; REPLICATION; PREVENTION; DISCOVERY; SITE;

D O I：

10.1016/j.bmcl.2024.129864

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/ p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

引用

页数：6

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