Literature DB >> 26985316

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials.

T G Murali Dhar1, Hai-Yun Xiao1, Jenny Xie1, Lois D Lehman-McKeeman1, Dauh-Rurng Wu1, Marta Dabros1, Xiaoxia Yang1, Tracy L Taylor1, Xia D Zhou1, Elizabeth M Heimrich1, Rochelle Thomas1, Kim W McIntyre1, Bethanne Warrack1, Hong Shi1, Paul C Levesque1, Jia L Zhu1, James Hennan1, Praveen Balimane1, Zheng Yang1, Anthony M Marino1, Georgia Cornelius1, Celia J D'Arienzo1, Arvind Mathur1, Ding Ren Shen1, Mary Ellen Cvijic1, Luisa Salter-Cid1, Joel C Barrish1, Percy H Carter1, Alaric J Dyckman1.   

Abstract

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.

Entities:  

Keywords:  GPCR; S1P1; S1P3; biased signaling

Year:  2016        PMID： 26985316      PMCID： PMC4789672          DOI： 10.1021/acsmedchemlett.5b00448

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  19 in total

1.  Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.

Authors:  Suzanne Mandala; Richard Hajdu; James Bergstrom; Elizabeth Quackenbush; Jenny Xie; James Milligan; Rosemary Thornton; Gan-Ju Shei; Deborah Card; CarolAnn Keohane; Mark Rosenbach; Jeffrey Hale; Christopher L Lynch; Kathleen Rupprecht; William Parsons; Hugh Rosen
Journal:  Science       Date:  2002-03-28       Impact factor: 47.728

2.  2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists.

Authors:  Martin H Bolli; Stefan Abele; Christoph Binkert; Roberto Bravo; Stephan Buchmann; Daniel Bur; John Gatfield; Patrick Hess; Christopher Kohl; Céline Mangold; Boris Mathys; Katalin Menyhart; Claus Müller; Oliver Nayler; Michael Scherz; Gunther Schmidt; Virginie Sippel; Beat Steiner; Daniel Strasser; Alexander Treiber; Thomas Weller
Journal:  J Med Chem       Date:  2010-05-27       Impact factor: 7.446

3.  Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Authors:  Ludwig Kappos; Jack Antel; Giancarlo Comi; Xavier Montalban; Paul O'Connor; Chris H Polman; Tomas Haas; Alexander A Korn; Goeril Karlsson; Ernst W Radue
Journal:  N Engl J Med       Date:  2006-09-14       Impact factor: 91.245

4.  Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.

Authors:  Takahide Nishi; Shojiro Miyazaki; Toshiyasu Takemoto; Keisuke Suzuki; Yukiko Iio; Katsuyoshi Nakajima; Takashi Ohnuki; Yumi Kawase; Futoshi Nara; Shinichi Inaba; Takashi Izumi; Hiroshi Yuita; Keiko Oshima; Hiromi Doi; Ryotaku Inoue; Wataru Tomisato; Takashi Kagari; Takaichi Shimozato
Journal:  ACS Med Chem Lett       Date:  2011-03-02       Impact factor: 4.345

5.  Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator.

Authors:  Shifeng Pan; Nathanael S Gray; Wenqi Gao; Yuan Mi; Yi Fan; Xing Wang; Tove Tuntland; Jianwei Che; Sophie Lefebvre; Yu Chen; Alan Chu; Klaus Hinterding; Anne Gardin; Peter End; Peter Heining; Christian Bruns; Nigel G Cooke; Barbara Nuesslein-Hildesheim
Journal:  ACS Med Chem Lett       Date:  2013-01-04       Impact factor: 4.345

6.  Engagement of S1P₁-degradative mechanisms leads to vascular leak in mice.

Authors:  Myat Lin Oo; Sung-Hee Chang; Shobha Thangada; Ming-Tao Wu; Karim Rezaul; Victoria Blaho; Sun-Il Hwang; David K Han; Timothy Hla
Journal:  J Clin Invest       Date:  2011-05-09       Impact factor: 14.808

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

Authors:  Daniel J Buzard; Sun Hee Kim; Luis Lopez; Andrew Kawasaki; Xiuwen Zhu; Jeanne Moody; Lars Thoresen; Imelda Calderon; Brett Ullman; Sangdon Han; Juerg Lehmann; Tawfik Gharbaoui; Dipanjan Sengupta; Lorene Calvano; Antonio Garrido Montalban; You-An Ma; Carleton Sage; Yinghong Gao; Graeme Semple; Jeff Edwards; Jeremy Barden; Michael Morgan; Weichao Chen; Khawja Usmani; Chuan Chen; Abu Sadeque; Ronald J Christopher; Jayant Thatte; Lixia Fu; Michelle Solomon; David Mills; Kevin Whelan; Hussien Al-Shamma; Joel Gatlin; Minh Le; Ibragim Gaidarov; Todd Anthony; David J Unett; Anthony Blackburn; Jaimie Rueter; Scott Stirn; Dominic P Behan; Robert M Jones
Journal:  ACS Med Chem Lett       Date:  2014-11-04       Impact factor: 4.345

8.  Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.

Authors:  Eric Legangneux; Anne Gardin; Donald Johns
Journal:  Br J Clin Pharmacol       Date:  2013-03       Impact factor: 4.335

Review 9.  Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis.

Authors:  Jerold Chun; Hans-Peter Hartung
Journal:  Clin Neuropharmacol       Date:  2010 Mar-Apr       Impact factor: 1.592

10.  Desensitization by progressive up-titration prevents first-dose effects on the heart: guinea pig study with ponesimod, a selective S1P1 receptor modulator.

Authors:  Markus Rey; Patrick Hess; Martine Clozel; Stéphane Delahaye; John Gatfield; Oliver Nayler; Beat Steiner
Journal:  PLoS One       Date:  2013-09-12       Impact factor: 3.240
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  6 in total

1.  Identification of potent tricyclic prodrug S1P1 receptor modulators.

Authors:  David Marcoux; Hai-Yun Xiao; T G Murali Dhar; Jenny Xie; Lois D Lehman-McKeeman; Dauh-Rurng Wu; Marta Dabros; Xiaoxia Yang; Tracy L Taylor; Xia D Zhou; Elizabeth M Heimrich; Rochelle Thomas; Kim W McIntyre; Hong Shi; Paul C Levesque; Huadong Sun; Zheng Yang; Anthony M Marino; Georgia Cornelius; Celia J D'Arienzo; Anuradha Gupta; Bala Pragalathan; Richard Rampulla; Arvind Mathur; Ding Ren Shen; Mary Ellen Cvijic; Luisa Salter-Cid; Louis J Lombardo; Percy H Carter; Alaric J Dyckman
Journal:  Medchemcomm       Date:  2016-11-25       Impact factor: 3.597

2.  Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P1) Modulators: Optimization of the PK, PD, and Safety Profiles.

Authors:  Zili Xiao; Michael G Yang; T G Murali Dhar; Hai-Yun Xiao; John L Gilmore; David Marcoux; Kim W McIntyre; Tracy L Taylor; Hong Shi; Paul C Levesque; Anthony M Marino; Georgia Cornelius; Arvind Mathur; Ding Ren Shen; Mary Ellen Cvijic; Lois D Lehman-McKeeman; Huadong Sun; Jenny H Xie; Percy H Carter; Alaric J Dyckman
Journal:  ACS Med Chem Lett       Date:  2020-08-11       Impact factor: 4.345

Review 3.  Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.

Authors:  Li Pang; Philip Sager; Xi Yang; Hong Shi; Frederick Sannajust; Mathew Brock; Joseph C Wu; Najah Abi-Gerges; Beverly Lyn-Cook; Brian R Berridge; Norman Stockbridge
Journal:  Circ Res       Date:  2019-10-10       Impact factor: 17.367

4.  The N,N,O-Trisubstituted Hydroxylamine Isostere and Its Influence on Lipophilicity and Related Parameters.

Authors:  Jarvis Hill; David Crich
Journal:  ACS Med Chem Lett       Date:  2022-04-20       Impact factor: 4.632

Review 5.  The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives.

Authors:  Alexandra Lucaciu; Robert Brunkhorst; Josef M Pfeilschifter; Waltraud Pfeilschifter; Julien Subburayalu
Journal:  Cells       Date:  2020-06-22       Impact factor: 6.600

Review 6.  G protein-coupled receptors: structure- and function-based drug discovery.

Authors:  Dehua Yang; Qingtong Zhou; Viktorija Labroska; Shanshan Qin; Sanaz Darbalaei; Yiran Wu; Elita Yuliantie; Linshan Xie; Houchao Tao; Jianjun Cheng; Qing Liu; Suwen Zhao; Wenqing Shui; Yi Jiang; Ming-Wei Wang
Journal:  Signal Transduct Target Ther       Date:  2021-01-08
  6 in total

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