ABSTRACT
An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.
Subject(s)
Cyclopentanes/chemistry , Neurokinin-1 Receptor Antagonists , Humans , Molecular Structure , Receptors, Neurokinin-1/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.
Subject(s)
Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Neurokinin-1 Receptor Antagonists , Water , Administration, Oral , Animals , CHO Cells , Cricetinae , Cyclopentanes/adverse effects , Cyclopentanes/chemical synthesis , Humans , Molecular Structure , Receptors, Neurokinin-1/genetics , Receptors, Neurokinin-1/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.
Subject(s)
Neurokinin-1 Receptor Antagonists , Spiro Compounds/pharmacologyABSTRACT
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.
