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.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Animals
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Colon / drug effects
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Colon / physiology
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Guinea Pigs
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Humans
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In Vitro Techniques
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Intestinal Absorption
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Male
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Molecular Conformation
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Muscle Contraction
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Radioligand Assay
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Receptors, Neurokinin-2 / agonists
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Receptors, Neurokinin-2 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Urinary Bladder / drug effects
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Urinary Bladder / physiology
Substances
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6-methylbenzo(b)thiophene-2-carboxylic acid (1-(1-benzyl-4-(4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl)butylcarbamoyl)cyclopentyl)amide
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Amides
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Furans
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Piperazines
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Receptors, Neurokinin-2
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Thiophenes