Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists.
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.
Fedi
Valentina
V
Menarini Ricerche S.p.a., Via dei Sette Santi 3, I-50131 Florence, Italy. vfedi@menarini-ricerche.it
Altamura
Maria
M
Catalioto
Rose-Marie
RM
Giannotti
Danilo
D
Giolitti
Alessandro
A
Giuliani
Sandro
S
Guidi
Antonio
A
Harmat
Nicholas J S
NJ
Lecci
Alessandro
A
Meini
Stefania
S
Nannicini
Rossano
R
Pasqui
Franco
F
Tramontana
Manuela
M
Triolo
Antonio
A
Maggi
Carlo Alberto
CA
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
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