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Dive into the research topics where Daniel Lundell is active.

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Featured researches published by Daniel Lundell.


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 | 2010

Discovery and SAR of hydantoin TACE inhibitors.

Wensheng Yu; Zhuyan Guo; Peter Orth; Madison; Liya Chen; Chaoyang Dai; Robert J. Feltz; Viyyoor Moopil Girijavallabhan; Seongkon Kim; Joseph A. Kozlowski; Brian J. Lavey; Dansu Li; Daniel Lundell; Xiaoda Niu; John J. Piwinski; Janeta Popovici-Muller; Razia Rizvi; Kristin E. Rosner; Bandarpalle B. Shankar; Neng-Yang Shih; M.A Siddiqui; Jing Sun; Ling Tong; Shelby Umland; Michael K.C. Wong; De-Yi Yang; Guowei Zhou

We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.


Bioorganic & Medicinal Chemistry Letters | 2010

Biaryl substituted hydantoin compounds as TACE inhibitors

Wensheng Yu; Ling Tong; Seong Heon Kim; Michael K.C. Wong; Lei Chen; De-Yi Yang; Bandarpalle B. Shankar; Brian J. Lavey; Guowei Zhou; Aneta Kosinski; Razia Rizvi; Dansu Li; Robert J. Feltz; John J. Piwinski; Kristin E. Rosner; Neng-Yang Shih; M. Arshad Siddiqui; Zhuyan Guo; Peter Orth; Himanshu Shah; Jing Sun; Shelby Umland; Daniel Lundell; Xiaoda Niu; Joseph A. Kozlowski

We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.


Bioorganic & Medicinal Chemistry Letters | 2012

A three-step protocol for lead optimization: Quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

Xianhai Huang; Xiaohong Zhu; Xiao Chen; Wei Zhou; Dong Xiao; Sylvia Degrado; Robert Aslanian; James Fossetta; Daniel Lundell; Fang Tian; Prashant Trivedi; Anandan Palani

A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.


Bioorganic & Medicinal Chemistry Letters | 2011

2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors.

Chaoyang Dai; Dansu Li; Janeta Popovici-Muller; Lianyun Zhao; Vinay Girijavallabhan; Kristin E. Rosner; Brian J. Lavey; Razia Rizvi; Bandarpalle B. Shankar; Michael K.C. Wong; Zhuyan Guo; Peter Orth; Corey O. Strickland; Jing Sun; Xiaoda Niu; Shiying Chen; Joseph A. Kozlowski; Daniel Lundell; John J. Piwinski; Neng-Yang Shih; M. Arshad Siddiqui

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.


Bioorganic & Medicinal Chemistry Letters | 2010

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases.

Vinay Girijavallabhan; Lei Chen; Chaoyang Dai; Robert J. Feltz; Luke Firmansjah; Dansu Li; Seong Heon Kim; Joseph A. Kozlowski; Brian J. Lavey; Aneta Kosinski; John J. Piwinski; Janeta Popovici-Muller; Razia Rizvi; Kristin E. Rosner; Banderpalle B. Shankar; Neng-Yang Shih; M. Arshad Siddiqui; Ling Tong; Michael K.C. Wong; De-Yi Yang; Liping Yang; Wensheng Yu; Guowei Zhou; Zhuyan Guo; Peter Orth; Vincent Madison; Hong Bian; Daniel Lundell; Xiaoda Niu; Himanshu Shah

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.


Bioorganic & Medicinal Chemistry Letters | 2013

Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors.

Dong Xiao; Anandan Palani; Xianhai Huang; Michael Sofolarides; Wei Zhou; Xiao Chen; Robert Aslanian; Zhuyan Guo; James Fossetta; Fang Tian; Prashant Trivedi; Peter Spacciapoli; Charles Whitehurst; Daniel Lundell

Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.


Bioorganic & Medicinal Chemistry Letters | 2010

Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands

Ling Tong; Bandarpalle B. Shankar; Lei Chen; Razia Rizvi; Joseph Kelly; Eric J. Gilbert; Chunli Huang; De-Yi Yang; Joseph A. Kozlowski; Neng-Yang Shih; W. Gonsiorek; R. William Hipkin; Asra Malikzay; Charles A. Lunn; Daniel Lundell

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB(2) receptor ligands with excellent selectivity over the CB(1) receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB(2) potency, selectivity and rat exposure.


Bioorganic & Medicinal Chemistry Letters | 2014

Discovery of a novel series of potent MK2 non-ATP competitive inhibitors using 1,2-substituted azoles as cis-amide isosteres.

Dong Xiao; Xiaohong Zhu; Michael Sofolarides; Sylvia Degrado; Ning Shao; Ashwin U. Rao; Xiao Chen; Robert Aslanian; James Fossetta; Fang Tian; Prashant Trivedi; Daniel Lundell; Anandan Palani

A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.


Bioorganic & Medicinal Chemistry Letters | 2010

Structure and activity relationships of tartrate-based TACE inhibitors.

Dansu Li; Janeta Popovici-Muller; David B. Belanger; John P. Caldwell; Chaoyang Dai; Maria David; Vinay Girijavallabhan; Brian J. Lavey; Joe F. Lee; Zhidan Liu; Rob Mazzola; Razia Rizvi; Kristin E. Rosner; Bandarpalle B. Shankar; Jim Spitler; Pauline C. Ting; Henry M. Vaccaro; Wensheng Yu; Guowei Zhou; Zhaoning Zhu; Xiaoda Niu; Jing Sun; Zhuyan Guo; Peter Orth; Shiying Chen; Joseph A. Kozlowski; Daniel Lundell; Vincent Madison; Brian A. McKittrick; John J. Piwinski

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.

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