title: Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine.
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.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology , Hwarangro 14-gil 5, Seoul 136-791, Korea ; Department of Chemistry, Korea University , Anam-ro 145, Seoul 136-701, Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Han
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology , Hwarangro 14-gil 5, Seoul 136-791, Korea.
authors.forename: Chiman
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Chemistry, Korea University , Anam-ro 145, Seoul 136-701, Korea.
authors.forename: Nakcheol
authors.initials: N
authors.lastname: Jeong
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology , Hwarangro 14-gil 5, Seoul 136-791, Korea.
authors.forename: Hoh-Gyu
authors.initials: HG
authors.lastname: Hahn
keywords: 3-aminoazetidines; Depression; bioisosterism; triple reuptake inhibitor