Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine

Title
Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine
Authors
한민수송치만정낙철한호규
Keywords
depression; triple reuptake inhibition; anti-depressant; 3-aminoazetidines; bioisosterism; monoamine hypothesis
Issue Date
2014-09
Publisher
ACS MEDICINAL CHEMISTRY LETTERS
Citation
VOL 5, NO 9, 999-1004
Abstract
For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.
URI
http://pubs.kist.re.kr/handle/201004/48128
ISSN
19485875
Appears in Collections:
KIST Publication > Article
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