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Bisubstrate ketone analogues as serotonin N-acetyltransferase inhibitors.

Abstract：

:Serotonin N-acetyltransferase, also called the melatonin rhythm enzyme, is thought to play an important regulatory role in circadian rhythm in animals and people. A series of analogues were synthesized in which indole and coenzyme A were linked via ketone tethers as designed inhibitors of this enzyme. These compounds were tested against purified serotonin N-acetyltransferase. The parent ketone compound was found to be as potent as an amide linked compound studied previously, suggesting that there are no key hydrogen bonds to the nitrogen atom of the corresponding substrate necessary for tight inhibition. Reduction of the parent ketone afforded the diastereomeric carbinol mixture which showed reduced inhibitory potency, arguing against tetrahedral analogue mimicry as an important inhibitory theme. Several conformationally constrained ketone analogues were synthesized and investigated, and the results indicated that directing the orientation of the two substrates within the bisubstrate system could be used to maximize enzyme inhibition.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kim CM,Cole PA

doi

10.1021/jm010049v

keywords:

subject

Has Abstract

pub_date

2001-07-19 00:00:00

pages

2479-85

issue

15

eissn

0022-2623

issn

1520-4804

pii

jm010049v

journal_volume

44

pub_type

杂志文章

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