Investigation of (E)-344-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

被引：39

作者：

Degorce, Sebastien L. ^{[1
,2
]}

Bailey, Andrew ^{[1
]}

Callis, Rowena ^{[3
]}

De Savi, Chris ^{[1
]}

Ducray, Richard ^{[2
]}

Lamontt, Gillian ^{[1
]}

MacFaul, Philip ^{[1
]}

Maudet, Mickael ^{[2
]}

Martin, Scott ^{[1
]}

Morgentin, Remy ^{[2
]}

Norman, Richard A. ^{[3
]}

Peru, Aurelien ^{[2
]}

Pink, Jennifer H. ^{[1
]}

Ple, Patrick A. ^{[2
]}

Roberts, Bryan ^{[1
]}

Scott, James S. ^{[1
]}

机构：

[1] AstraZeneca, Oncol Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Oncol Innovat Med Unit, Ctr Rech, F-51689 Reims 2, France

[3] AstraZeneca, Discovery Sci, Macclesfield SK10 4TG, Cheshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 08期

关键词：

PHARMACOLOGICAL EVALUATION; BREAST-CANCER; ANTIESTROGEN; DERIVATIVES; THERAPY; LIGANDS;

D O I：

10.1021/acs.jmedchem.5b00066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

引用

页码：3522 / 3533

页数：12

共 31 条

[1] Synthesis, pharmacological evaluation, and structure-activity relationships of benzopyran derivatives with potent SERM activity [J].

Amari, G ;

Armani, E ;

Ghirardi, S ;

Delcanale, M ;

Civelli, M ;

Caruso, PL ;

Galbiati, E ;

Lipreri, M ;

Rivara, S ;

Lodola, A ;

Mor, M .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (14) :3763-3782

[2]

Ariazi E.A., 2008, NUCL RECEPT DRUG TAR, P127, DOI [10.1002/9783527623297.ch5, DOI 10.1002/9783527623297.CH5]

[3]

Barlaam B. C., 2000, PCT INT APPL, Patent No. W02000062765

[4] Selective Estrogen Receptor Modulator medicinal chemistry at Merck. A review [J].

Blizzard, T. A. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (09) :792-812

[5]

Bridgland-Taylor M. H., 2006, Journal of Pharmacological and Toxicological Methods, V54, P189, DOI 10.1016/j.vascn.2006.02.003

[6] Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor [J].

Bury, PS ;

Christiansen, LB ;

Jacobsen, P ;

Jorgensen, AS ;

Kanstrup, A ;

Nærum, L ;

Bain, S ;

Fledelius, C ;

Gissel, B ;

Hansen, BS ;

Korsgaard, N ;

Thorpe, SM ;

Wassermann, K .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (01) :125-145

[7] A combined spectroscopic and crystallographic approach to probing drug-human serum albumin interactions [J].

Buttar, David ;

Colclough, Nicola ;

Gerhardt, Stefan ;

MacFaul, Philip A. ;

Phillips, Scott D. ;

Plowright, Alleyn ;

Whittamore, Paul ;

Tam, Kin ;

Maskos, Klaus ;

Steinbacher, Stefan ;

Steuber, Holger .

BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (21) :7486-7496

[8]

Callis R., 2015, J BIOMOL SCREENING

[9] Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight [J].

Camenisch, G ;

Alsenz, J ;

van de Waterbeemd, H ;

Folkers, G .

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 1998, 6 (04) :313-319

[10] CONTRASTING ENDOCRINE ACTIVITIES OF CIS AND TRANS ISOMERS IN A SERIES OF SUBSTITUTED TRIPHENYLETHYLENES [J].

HARPER, MJK ;

WALPOLE, AL .

NATURE, 1966, 212 (5057) :87-&

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