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α,α‐Cyclopentaneglycine Dipeptides Capped with Biaryls as Tachykinin NK 2 Receptor Antagonists
Author(s) -
Porcelloni Marina,
D'Andrea Piero,
Rossi Cristina,
Sisto Alessandro,
Ettorre Alessandro,
Madami Andrea,
Altamura Maria,
Giuliani Sandro,
Meini Stefania,
Fattori Daniela
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800018
Subject(s) - chemistry , dipeptide , antagonist , in vivo , receptor , stereochemistry , pharmacology , structure–activity relationship , in vitro , biochemistry , medicine , peptide , biology , microbiology and biotechnology
The NK 2 receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in‐house capped dipeptide libraries, we were able to identify a number of molecules with sub‐nanomolar binding affinity for the hNK 2 receptor. All were characterized by a rigid core structure with a strong constraint induced by an α,α‐cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in vitro functional assay, and a number of them showed significant in vivo activity after intravenous administration in our guinea pig model.