RESUMO
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.
Assuntos
Ciclopentanos/química , Ciclopentanos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Água , Administração Oral , Animais , Células CHO , Cricetinae , Ciclopentanos/efeitos adversos , Ciclopentanos/síntese química , Humanos , Estrutura Molecular , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ciclopentanos/química , Antagonistas dos Receptores de Neurocinina-1 , Humanos , Estrutura Molecular , Receptores da Neurocinina-1/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.
