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ABSTRACT: The concomitant use of silver oxide and catalytic amount of TBAF allowed the efficient and chemoselective coupling of readily available 4-chloro- and 4-methyl-2-trimethyl-silyl-pyridines with heteroaromatic and aromatic halides. Based on control experiments, a mechanism involving the formation of a pyridylsilver intermediate and TBAF recycling is postulated.
Organic & Biomolecular Chemistry 01/2011; 9(6):1768-73. · 3.70 Impact Factor
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Neil Moss,
Younggi Choi,
Derek Cogan,
Adam Flegg,
Andreas Kahrs,
Pui Loke,
Orietta Meyn,
Raj Nagaraja, Spencer Napier,
Ashley Parker,
J Thomas Peterson,
Philip Ramsden,
Christopher Sarko,
Donna Skow,
Josh Tomlinson,
Heather Tye,
Mark Whitaker
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ABSTRACT: We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Bioorganic & medicinal chemistry letters 05/2009; 19(8):2206-10. · 2.65 Impact Factor
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Matthew W Martin,
John Newcomb,
Joseph J Nunes,
David C McGowan,
David M Armistead,
Christina Boucher,
John L Buchanan,
William Buckner,
Lilly Chai,
Daniel Elbaum, [......],
Huilin Zhao,
Li Zhu,
Xiaotian Zhu,
Chiara Ghiron,
Patricia Amouzegh,
Monika Ermann,
James Jenkins,
David Johnston, Spencer Napier,
Eoin Power
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ABSTRACT: The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
Journal of Medicinal Chemistry 09/2006; 49(16):4981-91. · 5.25 Impact Factor
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Tetrahedron Letters 49(24):3939-3942. · 2.68 Impact Factor
