Design and Synthesis of an Orally Bioavailable and Selective Peptide Epoxyketone Proteasome Inhibitor (PR-047)

被引：224

作者：

Zhou, Han-Jie ^{[1
]}

Aujay, Monette A. ^{[1
]}

Bennett, Mark K. ^{[1
]}

Dajee, Maya ^{[1
]}

Demo, Susan D. ^{[1
]}

Fang, Ying ^{[1
]}

Ho, Mark N. ^{[1
]}

Jiang, Jing ^{[1
]}

Kirk, Christopher J. ^{[1
]}

Laidig, Guy J. ^{[1
]}

Lewis, Evan R. ^{[1
]}

Lu, Yan ^{[1
]}

Muchamuel, Tony ^{[1
]}

Parlati, Francesco ^{[1
]}

Ring, Eileen ^{[1
]}

Shenk, Kevin D. ^{[1
]}

Shields, Jamie ^{[1
]}

Shwonek, Peter J. ^{[1
]}

Stanton, Timothy ^{[1
]}

Sun, Congcong M. ^{[1
]}

Sylvain, Catherine ^{[1
]}

Woo, Tina M. ^{[1
]}

Yang, Jinfu ^{[1
]}

机构：

[1] Proteolix Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 09期

关键词：

MULTICATALYTIC PROTEINASE COMPLEX; REFRACTORY MULTIPLE-MYELOMA; NON-HODGKINS-LYMPHOMA; IRREVERSIBLE INHIBITOR; PHASE-II; BORTEZOMIB; POTENT; DEGRADATION; EPOXOMICIN; DRUGS;

D O I：

10.1021/jm801329v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and Non-Hodgkin's lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant: diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome: A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for improved dosing flexibility and patient convenience over, intravenously administered agents. The lead. compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (beta 5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral. administration at doses resulting in > 80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.

引用

页码：3028 / 3038

页数：11

共 44 条

[1] The proteasome: A suitable antineoplastic target [J].