The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

被引：62

作者：

Hagmann, WK ^{[1
]}

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

机构：

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

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

[3] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Comparat Med, Rahway, NJ 07065 USA

[5] Peptidogen Res & Co, Livermore, CA 94550 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 20期

关键词：

D O I：

10.1016/S0960-894X(01)00544-3

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：2709 / 2713

页数：5

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