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
Animals
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System
/ genetics
Dimethyl Sulfoxide
/ chemistry
Dogs
Drug Discovery
/ methods
Histamine H1 Antagonists, Non-Sedating
/ chemistry
Humans
Hydrogen Bonding
Inactivation, Metabolic
Loratadine
/ analogs & derivatives
Magnetic Resonance Spectroscopy
Metalloporphyrins
/ chemistry
Microsomes, Liver
/ drug effects
Rabbits
Recombinant Proteins
/ genetics
Structure-Activity Relationship
Tandem Mass Spectrometry
Tissue Distribution
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
09 07 2020
09 07 2020
Historique:
pubmed:
29
5
2020
medline:
28
11
2020
entrez:
29
5
2020
Statut:
ppublish
Résumé
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-
Identifiants
pubmed: 32462865
doi: 10.1021/acs.jmedchem.0c00483
doi:
Substances chimiques
Histamine H1 Antagonists, Non-Sedating
0
Metalloporphyrins
0
Recombinant Proteins
0
Loratadine
7AJO3BO7QN
Cytochrome P-450 Enzyme System
9035-51-2
Dimethyl Sulfoxide
YOW8V9698H
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM