Orally active purine-based inhibitors of the heat shock protein 90

被引：71

作者：

Biamonte, MA ^{[1
]}

Shi, JD ^{[1
]}

Hong, K ^{[1
]}

Hurst, DC ^{[1
]}

Zhang, L ^{[1
]}

Fan, JH ^{[1
]}

Busch, DJ ^{[1
]}

Karjian, PL ^{[1
]}

Maldonado, AA ^{[1
]}

Sensintaffar, JL ^{[1
]}

Yang, YC ^{[1
]}

Kamal, A ^{[1
]}

Lough, RE ^{[1
]}

Lundgren, K ^{[1
]}

Burrows, FJ ^{[1
]}

Timony, GA ^{[1
]}

Boehm, MF ^{[1
]}

Kasibhatla, SR ^{[1
]}

机构：

[1] Conforma Therapeut Corp, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 02期

关键词：

D O I：

10.1021/jm0503087

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC50 = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H3PO4 salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.

引用

页码：817 / 828

页数：12

共 39 条

[1] POTENTIAL PURINE ANTAGONISTS .28. PREPARATION OF VARIOUS BROMOPURINES [J].