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Dive into the research topics where Stuart B. Rosenblum is active.

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Featured researches published by Stuart B. Rosenblum.


BMC Immunology | 2012

A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

Chung Her Jenh; Mary Ann Cox; Long Cui; Eva Pia Reich; Lee Sullivan; Shu Cheng Chen; David Kinsley; Shiguang Qian; Seong Heon Kim; Stuart B. Rosenblum; Joseph A. Kozlowski; Paul J. Zavodny; Daniel Lundell

BackgroundThe CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.ResultsIn this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.ConclusionsSCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.


Bioorganic & Medicinal Chemistry Letters | 2011

I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.

Gopinadhan N. Anilkumar; Charles A. Lesburg; Oleg Selyutin; Stuart B. Rosenblum; Qingbei Zeng; Yueheng Jiang; Tin Yau Chan; Haiyan Pu; Henry M. Vaccaro; Li Wang; Frank Bennett; Kevin X. Chen; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Patrick Pinto; Mousumi Sannigrahi; Francisco Velazquez; Srikanth Venkatraman; Bancha Vibulbhan; Sony Agrawal; Nancy Butkiewicz; Boris Feld; Eric Ferrari; Zhiqing He; Chuan Kui Jiang; Robert E. Palermo; Patricia McMonagle; Hsueh-Cheng Huang; Neng Yang Shih

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.


Bioorganic & Medicinal Chemistry Letters | 2011

III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.

Seong Heon Kim; Gopinadhan N. Anilkumar; Lisa Guise Zawacki; Qingbei Zeng; De-Yi Yang; Yuefei Shao; Guizhen Dong; Xiaolian Xu; Wensheng Yu; Yueheng Jiang; Chung-Her Jenh; James W. Hall; Carolyn DiIanni Carroll; Doug W. Hobbs; John J. Baldwin; Brian F. Mcguinness; Stuart B. Rosenblum; Joseph A. Kozlowski; Bandarpalle B. Shankar; Neng-Yang Shih

The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.


Bioorganic & Medicinal Chemistry Letters | 2016

Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development

Anilkumar G. Nair; Qingbei Zeng; Oleg Selyutin; Stuart B. Rosenblum; Yueheng Jiang; De-Yi Yang; Kerry Keertikar; Guowei Zhou; Michael P. Dwyer; Seong Heon Kim; Bandarpalle B. Shankar; Wensheng Yu; Ling Tong; Lei Chen; Robert Mazzola; John P. Caldwell; Haiqun Tang; Melissa L. Allard; Ronald N. Buckle; Polivina Jolicia F Gauuan; Christian L. Holst; Gregory Scott Martin; Kannan P. Naicker; Samuel Vellekoop; Sony Agrawal; Rong Liu; Rong Kong; Paul Ingravallo; Ellen Xia; Ying Zhai

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.


Bioorganic & Medicinal Chemistry Letters | 2012

II. Novel HCV NS5B polymerase inhibitors: discovery of indole C2 acyl sulfonamides.

Gopinadhan N. Anilkumar; Oleg Selyutin; Stuart B. Rosenblum; Qingbei Zeng; Yueheng Jiang; Tin-Yau Chan; Haiyan Pu; Li Wang; Frank Bennett; Kevin X. Chen; Charles A. Lesburg; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Patrick Pinto; Mousumi Sannigrahi; Francisco Velazquez; Srikanth Venkatraman; Bancha Vibulbhan; Sony Agrawal; Eric Ferrari; Chuan-kui Jiang; Hsueh-Cheng Huang; Neng-Yang Shih; F. George Njoroge; Joseph A. Kozlowski

Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity.


Bioorganic & Medicinal Chemistry Letters | 2016

Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742.

Wensheng Yu; Craig A. Coburn; Anilkumar G. Nair; Michael Wong; Stuart B. Rosenblum; Guowei Zhou; Michael P. Dwyer; Ling Tong; Bin Hu; Bin Zhong; Jinglai Hao; Tao Ji; Shuai Zan; Seong Heon Kim; Qingbei Zeng; Oleg Selyutin; Lei Chen; Frédéric Massé; Sony Agrawal; Rong Liu; Ellen Xia; Ying Zhai; Stephanie Curry; Patricia McMonagle; Paul Ingravallo; Ernest Asante-Appiah; Mingxiang Lin; Joseph A. Kozlowski

Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.


Bioorganic & Medicinal Chemistry Letters | 2014

IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.

Anilkumar G. Nair; Michael K.C. Wong; Youheng Shu; Yueheng Jiang; Chung-Her Jenh; Seong Heon Kim; De-Yi Yang; Qingbei Zeng; Yuefei Shao; Lisa Guise Zawacki; Jingqi Duo; Brian F. Mcguinness; Carolyn DiIanni Carroll; Doug W. Hobbs; Neng-Yang Shih; Stuart B. Rosenblum; Joseph A. Kozlowski

The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.


Bioorganic & Medicinal Chemistry Letters | 2016

Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742

Wensheng Yu; Guowei Zhou; Craig A. Coburn; Qingbei Zeng; Ling Tong; Michael P. Dwyer; Bin Hu; Bin Zhong; Jinglai Hao; Tao Ji; Shuai Zan; Lei Chen; Robert Mazzola; Jae-Hun Kim; Deyou Sha; Oleg Selyutin; Stuart B. Rosenblum; Brian J. Lavey; Anilkumar G. Nair; Seong Heon Kim; Kerry Keertikar; Laura Rokosz; Sony Agrawal; Rong Liu; Ellen Xia; Ying Zhai; Stephanie Curry; Patricia McMonagle; Paul Ingravallo; Ernest Asante-Appiah

As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.


Bioorganic & Medicinal Chemistry Letters | 2016

Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors.

Michael P. Dwyer; Kerry Keertikar; Lei Chen; Ling Tong; Oleg Selyutin; Anilkumar G. Nair; Wensheng Yu; Guowei Zhou; Brian J. Lavey; De-Yi Yang; Michael Wong; Seong Heon Kim; Craig A. Coburn; Stuart B. Rosenblum; Qingbei Zeng; Yueheng Jiang; Bandarpalle B. Shankar; Razia Rizvi; Amin Nomeir; Rong Liu; Sony Agrawal; Ellen Xia; Rong Kong; Ying Zhai; Paul Ingravallo; Ernest Asante-Appiah; Joseph A. Kozlowski

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.


Bioorganic & Medicinal Chemistry Letters | 2016

Structure–activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors

Ling Tong; Wensheng Yu; Craig A. Coburn; Lei Chen; Oleg Selyutin; Qingbei Zeng; Michael P. Dwyer; Anilkumar G. Nair; Bandarpalle B. Shankar; Seong Heon Kim; De-Yi Yang; Stuart B. Rosenblum; Rebecca T. Ruck; Ian W. Davies; Bin Hu; Bin Zhong; Jinglai Hao; Tao Ji; Shuai Zan; Rong Liu; Sony Agrawal; Donna Carr; Stephanie Curry; Patricia McMonagle; Karin Bystol; Frederick Lahser; Paul Ingravallo; Shiying Chen; Ernest Asante-Appiah; Joseph A. Kozlowski

We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.

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