ABSTRACT
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Subject(s)
Lactams/chemistry , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/chemistry , Administration, Oral , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Models, Chemical , Molecular Structure , Nitrogen/chemistry , Protein Binding , Structure-Activity Relationship , Substance P/chemistry , Urea/chemistry , VomitingABSTRACT
A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki Subject(s)
Cyclobutanes/pharmacology
, Neurokinin-1 Receptor Antagonists
, Serotonin Antagonists/chemistry
, Serotonin Antagonists/pharmacology
, Animals
, Binding Sites
, Cyclobutanes/chemistry
, Stereoisomerism
, Structure-Activity Relationship
ABSTRACT
The total syntheses of natural agelastatin A and agelastatin B were accomplished via a strategy that utilized an alkynyliodonium salt --> alkylidenecarbene --> cyclopentene transformation to convert a relatively simple amino alcohol derivative to the functionalized core of the agelastatin system. Subsequent manipulations delivered debromoagelastatin, which served as a precursor to both agelastatin A and agelastatin B. Alkylidenecarbene insertion chemoselectivity issues were explored en route to the final targets.
