Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists

التفاصيل البيبلوغرافية
العنوان: Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists
المؤلفون: Peter Lin, Gary G. Chicchi, Julie A. DeMartino, Neil Collinson, Marc M. Kurtz, Susan Boyce, Robert J. DeVita, Alan Wheeldon, Jonathan R. Young, Stephen Moore, Emma J. Carlson, Kwei-Lan C. Tsao, Sander G. Mills, Karen Townson, George A. Doss, Gregori J. Morriello, Nadia M.J. Rupniak
المصدر: Bioorganic & Medicinal Chemistry. 16:2156-2170
بيانات النشر: Elsevier BV, 2008.
سنة النشر: 2008
مصطلحات موضوعية: Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Hydroxylation, Methylation, Biochemistry, Chemical synthesis, Pyrrolidine, chemistry.chemical_compound, Neurokinin-1 Receptor Antagonists, In vivo, Drug Discovery, Humans, Urea, Pyrroles, Molecular Biology, Molecular Structure, Bicyclic molecule, Chemistry, Organic Chemistry, Diastereomer, Stereoisomerism, Penetration (firestop), Receptors, Neurokinin-1, Bridged Bicyclo Compounds, Heterocyclic, Amides, In vitro, Lactam, Epoxy Compounds, Molecular Medicine
الوصف: Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
تدمد: 0968-0896
DOI: 10.1016/j.bmc.2007.11.081
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a07bdec5af551942f4ff8d7149d7c129
https://doi.org/10.1016/j.bmc.2007.11.081
Rights: CLOSED
رقم الانضمام: edsair.doi.dedup.....a07bdec5af551942f4ff8d7149d7c129
قاعدة البيانات: OpenAIRE
الوصف
تدمد:09680896
DOI:10.1016/j.bmc.2007.11.081