Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

被引：20

作者：

Doherty, GA ^{[1
]}

Yang, GX

Borges, E

Chang, LL

MacCoss, M

Tong, S

Kidambi, U

Egger, LA

McCauley, E

Van Riper, G

Mumford, RA

Schmidt, JA

Hagmann, WK

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Immunol & Rheumatol Res, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 11期

关键词：

D O I：

10.1016/S0960-894X(02)00211-1

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of substituted tetra hydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the a carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the P carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：1501 / 1505

页数：5

共 11 条

[1] The discovery of sulfonylated dipeptides as potent VLA-4 antagonists [J].

Hagmann, WK ;

Durette, PL ;

Lanza, T ;

Kevin, NJ ;

de Laszlo, SE ;

Kopka, HE ;

Young, D ;

Magriotis, PA ;

Li, B ;

Lin, LS ;

Yang, G ;

Kamenecka, T ;

Chang, LL ;

Wilson, J ;

MacCoss, M ;

Mills, SG ;

Van Riper, G ;

McCauley, E ;

Egger, LA ;

Kidambi, U ;

Lyons, K ;

Vincent, S ;

Stearns, R ;

Colletti, A ;

Teffera, J ;

Tong, S ;

Fenyk-Melody, J ;

Owens, K ;

Levorse, D ;

Kim, P ;

Schmidt, JA ;

Mumford, RA .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (20) :2709-2713

[2]

Katritzky AR, 1996, COMPREHENSIVE HETERO, V3

[3] Evidence for a prolonged role of alpha(4) integrin throughout active experimental allergic encephalomyelitis [J].

Keszthelyi, E ;

Karlik, S ;

Hyduk, S ;

Rice, GPA ;

Gordon, G ;

Yednock, T ;

Horner, H .

NEUROLOGY, 1996, 47 (04) :1053-1059

[4] Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents [J].

Lin, KC ;

Castro, AC .

CURRENT OPINION IN CHEMICAL BIOLOGY, 1998, 2 (04) :453-457

[5] Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses [J].

Lin, KC ;

Ateeq, HS ;

Hsiung, SH ;

Chong, LT ;

Zimmerman, CN ;

Castro, A ;

Lee, WC ;

Hammond, CE ;

Kalkunte, S ;

Chen, LL ;

Pepinsky, RB ;

Leone, DR ;

Sprague, AG ;

Abraham, WM ;

Gill, A ;

Lobb, RR ;

Adams, SP .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (05) :920-934

[6] Specific and dual antagonists of α4β1 and α4β7 integrins [J].

Lin, LS ;

Lanza, T ;

McCauley, E ;

Van Riper, G ;

Kidambi, U ;

Cao, J ;

Egger, LA ;

Mumford, RA ;

Schmidt, JA ;

MacCoss, M ;

Hagmann, WK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (02) :133-136

[7] ATTENUATION OF COLITIS IN THE COTTON-TOP TAMARIN BY ANTI-ALPHA-4 INTEGRIN MONOCLONAL-ANTIBODY [J].

PODOLSKY, DK ;

LOBB, R ;

KING, N ;

BENJAMIN, CD ;

PEPINSKY, B ;

SEHGAL, P ;

DEBEAUMONT, M .

JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (01) :372-380

[8]

Seiffge D, 1996, J RHEUMATOL, V23, P2086

[9] The effect of anti-α4 integrin antibody on brain lesion activity in MS [J].

Tubridy, N ;

Behan, PO ;

Capildeo, R ;

Chaudhuri, A ;

Forbes, R ;

Hawkins, CP ;

Hughes, RAC ;

Palace, J ;

Sharrack, B ;

Swingler, R ;

Young, C ;

Moseley, IF ;

MacManus, DG ;

Donoghue, S ;

Miller, DH .

NEUROLOGY, 1999, 53 (03) :466-472

[10]

WOLLWEBER H, 1976, EUR J MED CHEM, V11, P159

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