title: alpha,alpha-Cyclopentaneglycine dipeptides capped with biaryls as tachykinin NK(2) receptor antagonists.
abstract: 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 alpha,alpha-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.
authors.affiliation: Chemistry Department, Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia/Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Porcelloni
authors.forename: Piero
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sisto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ettorre
authors.forename: Andrea
authors.initials: A
authors.lastname: Madami
authors.forename: Maria
authors.initials: M
authors.lastname: Altamura
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Daniela
authors.initials: D
authors.lastname: Fattori
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000737:chemistry
chemical_list: D001713:Biphenyl Compounds; D003517:Cyclopentanes; D004151:Dipeptides; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C088015:benzothiophene; D005998:Glycine