PTP1B inhibitors: Synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

被引：23

作者：

Holmes, Christopher P. ^{[1
]}

Li, Xianfeng ^{[1
]}

Pan, Yijun ^{[1
]}

Xu, Caiding ^{[1
]}

Bhandari, Ashok ^{[1
]}

Moody, Claire M. ^{[1
]}

Miguel, Joy A. ^{[1
]}

Ferla, Steven W. ^{[1
]}

De Francisco, M. Nuria ^{[1
]}

Frederick, Brian T. ^{[1
]}

Zhou, Siqun ^{[1
]}

Macher, Natalie ^{[1
]}

Jang, Larry ^{[1
]}

Irvine, Jennifer D. ^{[1
]}

Grove, J. Russell ^{[1
]}

机构：

[1] Affymax Inc, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 08期

关键词：

PTP1B; phosphatase; bioisostere; sulfonamide;

D O I：

10.1016/j.bmcl.2008.03.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono-or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics. (C) 2008 Elsevier Ltd. All rights reserved.

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收藏

页码：2719 / 2724

页数：6

相关论文

共 29 条

[1] 2-(Oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases [J].

Andersen, HS ;

Iversen, LF ;

Jeppesen, CB ;

Branner, S ;

Norris, K ;

Rasmussen, HB ;

Moller, KB ;

Moller, NPH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (10) :7101-7108

[2] CRYSTAL-STRUCTURE OF HUMAN PROTEIN-TYROSINE-PHOSPHATASE 1B [J].

BARFORD, D ;

FLINT, AJ ;

TONKS, NK .

SCIENCE, 1994, 263 (5152) :1397-1404

[3] Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin actions [J].

Bleasdale, JE ;

Ogg, D ;

Palazuk, BJ ;

Jacob, CS ;

Swanson, ML ;

Wang, XY ;

Thompson, DP ;

Conradi, RA ;

Mathews, WR ;

Laborde, AL ;

Stuchly, CW ;

Heijbel, A ;

Bergdahl, K ;

Bannow, CA ;

Smith, CW ;

Svensson, C ;

Liljebris, C ;

Schostarez, HJ ;

May, PD ;

Stevens, FC ;

Larsen, SD .

BIOCHEMISTRY, 2001, 40 (19) :5642-5654

[4] 4'-O-[2-(2-fluoromalonyl)]-L-tyrosine: A phosphotyrosyl mimic for the preparation of signal transduction inhibitory peptides [J].

Burke, TR ;

Ye, B ;

Akamatsu, M ;

Ford, H ;

Yan, XJ ;

Kole, HK ;

Wolf, G ;

Shoelson, SE ;

Roller, PP .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (05) :1021-1027

[5] Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design [J].

Burke, TR ;

Ye, B ;

Yan, XJ ;

Wang, SM ;

Jia, ZC ;

Chen, L ;

Zhang, ZY ;

Barford, D .

BIOCHEMISTRY, 1996, 35 (50) :15989-15996

[6] POTENT INHIBITION OF INSULIN-RECEPTOR DEPHOSPHORYLATION BY A HEXAMER PEPTIDE-CONTAINING THE PHOSPHOTYROSYL MIMETIC F(2)PMP [J].

BURKE, TR ;

KOLE, HK ;

ROLLER, PP .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 204 (01) :129-134

[7] α-Ketocarboxylic acid-based inhibitors of protein tyrosine phosphatases [J].

Chen, YT ;

Onaran, MB ;

Doss, CJ ;

Seto, CT .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (14) :1935-1938

[8] The development of potent non-peptidic PTP-1B inhibitors [J].

Dufresne, C ;

Roy, P ;

Wang, ZY ;

Asante-Appiah, E ;

Cromlish, W ;

Boie, Y ;

Forghani, F ;

Desmarais, S ;

Wang, QP ;

Skorey, K ;

Waddleton, D ;

Ramachandran, C ;

Kennedy, BP ;

Xu, LJ ;

Gordon, R ;

Chan, CC ;

Leblanc, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (04) :1039-1042

[9] Examination of novel non-phosphorus-containing phosphotyrosyl mimetics against protein-tyrosine phosphatase-1B and demonstration of differential affinities toward Grb2 SH2 domains [J].

Gao, Y ;

Wu, L ;

Luo, JH ;

Guo, R ;

Yang, D ;

Zhang, ZY ;

Burke, TR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (09) :923-927

[10] Discovery and structure-activity relationships of novel sulfonamides as potent PTP1B inhibitors [J].

Holmes, CP ;

Li, XF ;

Pan, YJ ;

Xu, CD ;

Bhandari, A ;

Moody, CM ;

Miguel, JA ;

Ferla, SW ;

De Francisco, MN ;

Frederick, BT ;

Zhou, SQ ;

Macher, N ;

Jang, L ;

Irvine, JD ;

Grove, JR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (19) :4336-4341