title: Structure-activity relationships of 6-methyl-benzo[b]thiophene-2-carboxylic acid (1-[(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl]cyclopentyl)amide, potent antagonist of the neurokinin-2 receptor.
abstract: As part of a project aimed at the identification of a series of small, orally available antagonists for the hNK(2) receptor, starting from one of our capped dipeptide libraries, we succeeded in the chemical optimization of the first identified leads, finally producing a class of molecules with significant activity in our animal model after iv administration. We herein report the results of further chemical modifications made to reduce the overall peptide character of this series and the consequent improvement of their in vivo antagonist activity. The present work identified 6-methylbenzo[b]thiophene-2-carboxylic acid (1-[(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl]cyclopentyl)amide (10i), endowed with subnanomolar potency in all the in vitro tests and being highly potent and of long duration upon in vivo testing after both iv and id dosing.
authors.affiliation: Menarini Ricerche, Rome, Italy. Dfattori@menarini-ricerche.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Fattori
authors.forename: Marina
authors.initials: M
authors.lastname: Porcelloni
authors.forename: Piero
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Catalioto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ettorre
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Elena
authors.initials: E
authors.lastname: Marastoni
authors.forename: Sandro
authors.initials: S
authors.lastname: Mauro
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Maria
authors.initials: M
authors.lastname: Altamura
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: C550161:6-methylbenzo(b)thiophene-2-carboxylic acid (1-(1-benzyl-4-(4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl)butylcarbamoyl)cyclopentyl)amide; D000577:Amides; D005663:Furans; D010879:Piperazines; D018041:Receptors, Neurokinin-2; D013876:Thiophenes