Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure-Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H
| Autor: | Manjinder S, Lall, Asser, Bassyouni, James, Bradow, Maria, Brown, Mark, Bundesmann, Jinshan, Chen, Gregory, Ciszewski, Anne E, Hagen, Dennis, Hyek, Stephen, Jenkinson, Bo, Liu, R Scott, Obach, Senliang, Pan, Usa, Reilly, Neal, Sach, Daniel J, Smaltz, Douglas K, Spracklin, Jeremy, Starr, Melissa, Wagenaar, Gregory S, Walker |
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| Rok vydání: | 2020 |
| Předmět: |
Histamine H1 Antagonists
Non-Sedating Magnetic Resonance Spectroscopy Metalloporphyrins Hydrogen Bonding Loratadine Recombinant Proteins Structure-Activity Relationship Dogs Cytochrome P-450 Enzyme System Tandem Mass Spectrometry Drug Discovery Inactivation Metabolic Microsomes Liver Animals Humans Dimethyl Sulfoxide Tissue Distribution Rabbits Chromatography High Pressure Liquid |
| Zdroj: | Journal of medicinal chemistry. 63(13) |
| ISSN: | 1520-4804 |
| Popis: | An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO |
| Databáze: | OpenAIRE |
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