Arylsulfonamide pyrimidines as VLA-4 antagonists

被引：6

作者：

Xu, Ying-zi ^{[1
]}

Konradi, Andrei W. ^{[1
]}

Bard, Frederique ^{[2
]}

Dappen, Michael ^{[1
]}

Dofiles, Lilibeth ^{[3
]}

Dreyer, Mark ^{[4
]}

Gallager, Ian ^{[2
]}

Garrido, Caroline ^{[2
]}

Krimm, Mike ^{[3
]}

Liao, Zhenmei ^{[3
]}

Messersmith, Elizabeth ^{[3
]}

Mutter, Linda ^{[4
]}

Pleiss, Michael A. ^{[1
]}

Samant, Bhushan ^{[4
]}

Semko, Christopher M. ^{[1
]}

Smith, Jennifer ^{[1
]}

Stappenbeck, Frank ^{[1
]}

Stupi, Brian ^{[1
]}

Vandervert, Chris ^{[2
]}

Welch, Brent ^{[2
]}

Wipke, Brian ^{[3
]}

Yednock, Ted ^{[2
]}

机构：

[1] Elan Pharmaceut Inc, Dept Chem Sci, San Francisco, CA 94080 USA

[2] Elan Pharmaceut Inc, Dept Biol, San Francisco, CA 94080 USA

[3] Elan Pharmaceut Inc, Dept Pharmacol, San Francisco, CA 94080 USA

[4] Elan Pharmaceut Inc, Dept DMPK, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 10期

关键词：

alpha(4)beta(1); VLA-4; Antagonist; Orally available; CIA model; EAE model; INTEGRIN ANTAGONISTS; ALPHA-4; INTEGRIN; SMALL-MOLECULE; AMIDE BOND; INFLAMMATION; ARTHRITIS; MODEL;

D O I：

10.1016/j.bmcl.2013.03.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3070 / 3074

页数：5

共 18 条

[1] A small-molecule, tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep [J].

Abraham, WM ;

Gill, A ;

Ahmed, A ;

Sielczak, MW ;

Lauredo, IT ;

Botinnikova, Y ;

Lin, KC ;

Pepinsky, B ;

Leone, DR ;

Lobb, RR ;

Adams, SP .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2000, 162 (02) :603-611

[2] Animal models of arthritis: Relevance to human disease [J].

Bendele, A ;

McComb, J ;

Gould, T ;

McAbee, T ;

Sennello, G ;

Chlipala, E ;

Guy, M .

TOXICOLOGIC PATHOLOGY, 1999, 27 (01) :134-142

[3] Constraining the amide bond in N-Sulfonylated dipeptide VLA-4 antagonists [J].

Chang, Linda L. ;

Yang, Ginger X. ;

McCauley, Ermengilda ;

Mumford, Richard A. ;

Schmidt, John A. ;

Hagmann, William K. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (05) :1688-1691

[4] Integrins as therapeutic targets: lessons and opportunities [J].

Cox, Dermot ;

Brennan, Marian ;

Moran, Niamh .

NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (10) :804-820

[5] Synthesis and SAR of pyridazinone-substituted phenylalanine amide α4 integrin antagonists [J].

Gong, Yong ;

Barbay, J. Kent ;

Kimball, Edward S. ;

Santulli, Rosemary J. ;

Fisher, M. Carolyn ;

Dyatkin, Alexey B. ;

Miskowski, Tamara A. ;

Hornby, Pamela J. ;

He, Wei .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (04) :1331-1335

[6] The identification and optimization of orally efficacious, small molecule VLA-4 antagonists [J].

Huryn, DM ;

Konradi, AW ;

Ashwell, S ;

Freedman, SB ;

Lombardo, LJ ;

Pleiss, MA ;

Thorsett, ED ;

Yednock, T ;

Kennedy, JD .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (14) :1473-1484

[7] Alpha 4 integrin antagonists [J].

Jackson, DY .

CURRENT PHARMACEUTICAL DESIGN, 2002, 8 (14) :1229-1253

[8] Amidines as amide bond replacements in VLA-4 antagonists [J].

Kamenecka, TM ;

Park, YJ ;

Lin, LS ;

de Laszlo, S ;

McCauley, ED ;

Van Riper, G ;

Egger, L ;

Kidambi, U ;

Mumford, RA ;

Tong, S ;

Tang, W ;

Colletti, A ;

Teffera, Y ;

Stearns, R ;

MacCross, M ;

Schmidt, JA ;

Hagmann, WK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) :2323-2326

[9] CHARACTERIZATION OF A MURINE MODEL OF ALLERGIC PULMONARY INFLAMMATION [J].

KUNG, TT ;

JONES, H ;

ADAMS, GK ;

UMLAND, SP ;

KREUTNER, W ;

EGAN, RW ;

CHAPMAN, RW ;

WATNICK, AS .

INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY, 1994, 105 (01) :83-90

[10] Selection of a 2-azabicyclo[2.2.2]octane-based α4β1 integrin antagonist as an inhaled anti-asthmatic agent [J].

Lawson, Edward C. ;

Santulli, Rosemary J. ;

Dyatkin, Alexey B. ;

Ballentine, Scott A. ;

Abraham, William M. ;

Rudman, Sandra ;

Page, Clive P. ;

de Garavilla, Lawrence ;

Damiano, Bruce P. ;

Kinney, William A. ;

Maryanoff, Bruce E. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (12) :4208-4216

← 1 2 →