Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

被引：54

作者：

Buzard, Daniel J. ^{[1
]}

Kim, Sun Hee ^{[1
]}

Lopez, Luis ^{[1
]}

Kawasaki, Andrew ^{[1
]}

Zhu, Xiuwen ^{[1
]}

Moody, Jeanne ^{[1
]}

Thoresen, Lars ^{[1
]}

Calderon, Imelda ^{[1
]}

Ullman, Brett ^{[1
]}

Han, Sangdon ^{[1
]}

Lehmann, Juerg ^{[1
]}

Gharbaoui, Tawfik ^{[1
]}

Sengupta, Dipanjan ^{[1
]}

Calvano, Lorene ^{[1
]}

Montalban, Antonio Garrido ^{[1
]}

Ma, You-An ^{[1
]}

Sage, Carleton ^{[1
]}

Gao, Yinghong ^{[1
]}

Semple, Graeme ^{[1
]}

Edwards, Jeff ^{[1
]}

Barden, Jeremy ^{[1
]}

Morgan, Michael ^{[1
]}

Chen, Weichao ^{[1
]}

Usmani, Khawja ^{[1
]}

Chen, Chuan ^{[1
]}

Sadeque, Abu ^{[1
]}

Christopher, Ronald J. ^{[1
]}

Thatte, Jayant ^{[1
]}

Fu, Lixia ^{[1
]}

Solomon, Michelle ^{[1
]}

Mills, David ^{[1
]}

Whelan, Kevin ^{[1
]}

Al-Shamma, Hussien ^{[1
]}

Gatlin, Joel ^{[1
]}

Minh Le ^{[1
]}

Gaidarov, Ibragim ^{[1
]}

Anthony, Todd ^{[1
]}

Unett, David J. ^{[1
]}

Blackburn, Anthony ^{[1
]}

Rueter, Jaimie ^{[1
]}

Stirn, Scott ^{[1
]}

Behan, Dominic P. ^{[1
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut Inc, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 12期

关键词：

Sphingosine-1-phosphate; S1P(1); APD334; gilenya; FTY720; fingolimod; MULTIPLE-SCLEROSIS; FINGOLIMOD FTY720; HEART-RATE; AGONISTS; S1P(1); MODULATOR; EFFICACY; DISEASE; POTENT; MODEL;

D O I：

10.1021/ml500389m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P(1) receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P(1) and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

引用

页码：1313 / 1317

页数：5

共 24 条

[1]

[Anonymous], 2013, Inflamm. Regen

[2] Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology [J].

Brinkmann, Volker .

PHARMACOLOGY & THERAPEUTICS, 2007, 115 (01) :84-105

[3] Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists [J].

Buzard, Daniel ;

Han, Sangdon ;

Thoresen, Lars ;

Moody, Jeanne ;

Lopez, Luis ;

Kawasaki, Andrew ;

Schrader, Thomas ;

Sage, Carleton ;

Gao, Yinghong ;

Edwards, Jeff ;

Barden, Jeremy ;

Thatte, Jayant ;

Fu, Lixia ;

Solomon, Michelle ;

Liu, Ling ;

Al-Shamma, Hussien ;

Gatlin, Joel ;

Le, Minh ;

Xing, Charles ;

Espinola, Sheryll ;

Jones, Robert M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (19) :6013-6018

[4] Fused tricyclic indoles as S1P1 agonists with robust efficacy in animal models of autoimmune disease [J].

Buzard, Daniel J. ;

Han, Sangdon ;

Lopez, Luis ;

Kawasaki, Andrew ;

Moody, Jeanne ;

Thoresen, Lars ;

Ullman, Brett ;

Lehmann, Juerg ;

Calderon, Imelda ;

Zhu, Xiuwen ;

Gharbaoui, Tawfik ;

Sengupta, Dipanjan ;

Krishnan, Ashwin ;

Gao, Yinghong ;

Edwards, Jeff ;

Barden, Jeremy ;

Morgan, Michael ;

Usmani, Khawja ;

Chen, Chuan ;

Sadeque, Abu ;

Thatte, Jayant ;

Solomon, Michelle ;

Fu, Lixia ;

Whelan, Kevin ;

Liu, Ling ;

Al-Shamma, Hussien ;

Gatlin, Joel ;

Le, Minh ;

Xing, Charles ;

Espinola, Sheryll ;

Jones, Robert M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (13) :4404-4409

[5] FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation [J].

Choi, Ji Woong ;

Gardell, Shannon E. ;

Herr, Deron R. ;

Rivera, Richard ;

Lee, Chang-Wook ;

Noguchi, Kyoko ;

Teo, Siew Teng ;

Yung, Yun C. ;

Lu, Melissa ;

Kennedy, Grace ;

Chun, Jerold .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (02) :751-756

[6]

Chun J, 2011, DISCOV MED, V12, P213

[7] Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis [J].

Chun, Jerold ;

Hartung, Hans-Peter .

CLINICAL NEUROPHARMACOLOGY, 2010, 33 (02) :91-101

[8] Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS) [J].

Constantinescu, Cris S. ;

Farooqi, Nasr ;

O'Brien, Kate ;

Gran, Bruno .

BRITISH JOURNAL OF PHARMACOLOGY, 2011, 164 (04) :1079-1106

[9] Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose [J].

Demont, Emmanuel H. ;

Arpino, Sandra ;

Bit, Rino A. ;

Campbell, Colin A. ;

Deeks, Nigel ;

Desai, Sapna ;

Dowell, Simon J. ;

Gaskin, Pam ;

Gray, James R. J. ;

Harrison, Lee A. ;

Haynes, Andrea ;

Heightman, Tom D. ;

Holmes, Duncan S. ;

Humphreys, Philip G. ;

Kumar, Umesh ;

Morse, Mary A. ;

Osborne, Greg J. ;

Panchal, Terry ;

Philpott, Karen L. ;

Taylor, Simon ;

Watson, Robert ;

Willis, Robert ;

Witherington, Jason .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (19) :6724-6733

[10] Recent Advances in the Discovery and Development of Sphingosine-1-Phosphate-1 Receptor Agonists [J].

Dyckman, Alaric J. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 47, 2012, 47 :195-207

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