Discovery of Aryloxy Tetramethylcyclobutanes as Novel Androgen Receptor Antagonists

被引：55

作者：

Guo, Chuangxing ^{[1
]}

Linton, Angelica ^{[1
]}

Kephart, Susan ^{[1
]}

Ornelas, Martha ^{[1
]}

Pairish, Mason ^{[1
]}

Gonzalez, Javier ^{[1
]}

Greasley, Samantha ^{[1
]}

Nagata, Asako ^{[1
]}

Burke, Benjamin J. ^{[1
]}

Edwards, Martin ^{[1
]}

Hosea, Natilie ^{[2
]}

Kang, Ping ^{[2
]}

Hu, Wenyue ^{[3
]}

Engebretsen, Jon ^{[4
]}

Briere, David ^{[4
]}

Shi, Manli ^{[4
]}

Gukasyan, Hovik ^{[5
]}

Richardson, Paul ^{[1
]}

Dack, Kevin ^{[6
]}

Underwood, Toby ^{[6
]}

Johnson, Patrick ^{[6
]}

Morell, Andrew ^{[6
]}

Felstead, Robert ^{[6
]}

Kuruma, Hidetoshi ^{[7
]}

Matsimoto, Hiroaki ^{[7
]}

Zoubeidi, Amina ^{[7
]}

Gleave, Martin ^{[7
]}

Los, Gerrit ^{[4
]}

Fanjul, Andrea N. ^{[4
]}

机构：

[1] Pfizer Worldwide Res & Dev, Oncol Med Chem, San Diego, CA 92121 USA

[2] Pfizer Worldwide Res & Dev, PDM, San Diego, CA 92121 USA

[3] Pfizer Worldwide Res & Dev, DSRD, San Diego, CA 92121 USA

[4] Pfizer Worldwide Res & Dev, Oncol Res Unit, San Diego, CA 92121 USA

[5] Pfizer Worldwide Res & Dev, Pharmaceut Sci Res Enabling Grp, San Diego, CA 92121 USA

[6] Pfizer Worldwide Res & Dev, World Wide Med Chem, Sandwich CT13 9NJ, Kent, England

[7] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 21期

关键词：

RESISTANT PROSTATE-CANCER; LIGAND-BINDING DOMAIN; MOLECULAR DETERMINANTS; RECOGNITION; IDENTIFICATION; ANTIANDROGEN; INHIBITOR; SERIES;

D O I：

10.1021/jm201059s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.

引用

页码：7693 / 7704

页数：12

共 24 条

[1]

[Anonymous], 2009, GLID VERS 5 5

[2] Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer [J].

Attar, Ricardo M. ;

Jure-Kunkel, Maria ;

Balog, Aaron ;

Cvijic, Mary Ellen ;

Dell-John, Janet ;

Rizzo, Cheryl A. ;

Schweizer, Liang ;

Spires, Thomas E. ;

Platero, J. Suso ;

Obermeier, Mary ;

Shan, Weifang ;

Salvati, Mark E. ;

Foster, William R. ;

Dinchuk, Joseph ;

Chen, Shen-Jue ;

Vite, Gregory ;

Kramer, Robert ;

Gottardis, Marco M. .

CANCER RESEARCH, 2009, 69 (16) :6522-6530

[3] Molecular determinants of resistance to antiandrogen therapy [J].

Chen, CD ;

Welsbie, DS ;

Tran, C ;

Baek, SH ;

Chen, R ;

Vessella, R ;

Rosenfeld, MG ;

Sawyers, CL .

NATURE MEDICINE, 2004, 10 (01) :33-39

[4] Targeting the androgen receptor pathway in prostate cancer [J].

Chen, Yu ;

Sawyers, Charles L. ;

Scher, Howard I. .

CURRENT OPINION IN PHARMACOLOGY, 2008, 8 (04) :440-448

[5] Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity [J].

De Jesus-Tran, KP ;

Cote, PL ;

Cantin, L ;

Blanchet, J ;

Labrie, F ;

Breton, R .

PROTEIN SCIENCE, 2006, 15 (05) :987-999

[6] SINGLE BASE MUTATIONS IN THE HUMAN ANDROGEN RECEPTOR GENE CAUSING COMPLETE ANDROGEN INSENSITIVITY - RAPID DETECTION BY A MODIFIED DENATURING GRADIENT GEL-ELECTROPHORESIS TECHNIQUE [J].

DEBELLIS, A ;

QUIGLEY, CA ;

CARIELLO, NF ;

ELAWADY, MK ;

SAR, M ;

LANE, MV ;

WILSON, EM ;

FRENCH, FS .

MOLECULAR ENDOCRINOLOGY, 1992, 6 (11) :1909-1920

[7]

Gehlhaar D., 1999, Rational Drug Design, V719, P292

[8] MOLECULAR RECOGNITION OF THE INHIBITOR AG-1343 BY HIV-1 PROTEASE - CONFORMATIONALLY FLEXIBLE DOCKING BY EVOLUTIONARY PROGRAMMING [J].

GEHLHAAR, DK ;

VERKHIVKER, GM ;

REJTO, PA ;

SHERMAN, CJ ;

FOGEL, DB ;

FOGEL, LJ ;

FREER, ST .

CHEMISTRY & BIOLOGY, 1995, 2 (05) :317-324

[9] Recognition and accommodation at the androgen receptor coactivator binding interface [J].

Hur, E ;

Pfaff, SJ ;

Payne, ES ;

Gron, H ;

Buehrer, BM ;

Fletterick, RJ .

PLOS BIOLOGY, 2004, 2 (09) :1303-1312

[10] Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC) [J].

Jung, Michael E. ;

Ouk, Samedy ;

Yoo, Dongwon ;

Sawyers, Charles L. ;

Chen, Charlie ;

Tran, Chris ;

Wongvipat, John .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) :2779-2796

← 1 2 3 →