title: Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists.
abstract: Starting from 1 (MEN14268), a selective tachykinin NK2 receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral alpha,alpha-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.
authors.affiliation: Menarini Ricerche S.p.a., Via dei Sette Santi 3, I-50131 Florence, Italy. vfedi@menarini-ricerche.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Fedi
authors.forename: Maria
authors.initials: M
authors.lastname: Altamura
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Catalioto
authors.forename: Danilo
authors.initials: D
authors.lastname: Giannotti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giolitti
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Antonio
authors.initials: A
authors.lastname: Guidi
authors.forename: Nicholas J S
authors.initials: NJ
authors.lastname: Harmat
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lecci
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Rossano
authors.initials: R
authors.lastname: Nannicini
authors.forename: Franco
authors.initials: F
authors.lastname: Pasqui
authors.forename: Manuela
authors.initials: M
authors.lastname: Tramontana
authors.forename: Antonio
authors.initials: A
authors.lastname: Triolo
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007267:Injections; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: C516535:6-methylbenzo(b)thiophene-2-carboxylic acid (1-(2-phenyl-((1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl)carbamoyl)ethylcarbamoyl)cyclophenyl)amide; D003517:Cyclopentanes; D004151:Dipeptides; D010880:Piperidines; D011714:Pyrans; D018041:Receptors, Neurokinin-2; D013876:Thiophenes