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. KEYWORDS: Depression, triple reuptake inhibitor, 3-aminoazetidines, bioisosterism D epression is one of the leading diseases worldwide. Epidemiological studies demonstrate that depressive disorders are highly prevalent; it is estimated that, in general, the lifetime prevalence of major depression was 20% in women and 10% in men. The incidence of depression has risen every year since the early 20th century. There are probably many reasons for this rise, though most studies point to significant socioeconomic changes and complicated circumstances experienced by the younger generation. Pathophysiologically, the cause of depression is commonly associated with a deficiency of monoamine neurotransmitters (serotonin (5-HT), norepinephrine (NE), and dopamine (DA)) in the brain, and a number of antidepressants aim to increase the levels of these neurotransmitters in the synapses.1−4 Since the launch of the first selective serotonin reuptake inhibitors (SSRIs) in the 1980s, second generation antidepressants such as dual 5-HT and NE reuptake inhibitors (SNRIs) or NE and DA reuptake inhibitors (NDRIs) with enhanced properties have been substituted to tricyclic derivatives or monoamine oxidase inhibitors. 5,6 However, a very large percentage of patients treated with SSRIs or SNRIs show partial responses and remission rate around 30%.7 Additionally, the associated side effects such as insomnia, sexual dysfunction, and elevated blood pressure hamper their efficacy. 8,9 In modern therapies for depression, one important strategy to improve the efficacy and/or reduce the delay in the onset of their action is the addition of a DA component to SSRIs or SNRIs. Recent study results support the effect of DA in depression.10 NDRI bupropion enhanced the antidepressant actions of SSRIs and SNRIs in humans, 5,11 and suppression of DA reuptake enhances sexual function and may improve cognitive performance.1,12 An important recent development has been achieved with the discovery of triple reuptake inhibitors (TRIs), broad spectrum antidepressants that are capable of...

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

“…39 Like propellane systems, access to amino-azetidines is largely limited to a building-block approach that relies on the multistep synthesis of protected azetidinones. Azabicyclobutane (ABB, 7 ) was first prepared by Funke in 1969 and has been used sporadically ever since as a method for preparing functionalized azetidines.…”

A Single-Step Synthesis of Azetidine-3-amines

“…The filtrate was concentrated, and the residue was purified by silica gel flash column chromatography using 5:95 to 3:7 ethyl acetate / hexanes as eluent to give 1-(1benzhydrylazetidin-3-yl)-4-(3-(trifluoromethyl)phenyl)piperazine as an off-white solid (397 mg, 7, 128.6, 127.6, 127.3, 124.4 (q, J = 272 Hz, 1C), 118.8, 116.0 (q, J = 3 Hz, 1C), 112.3 (q, J = 4 Hz, 1C), 78.3, 58.2, 54.8, 49.8, 48.4. 8,142.24,142.16,141.2,128.9,128.52,128.49,127.9,127.6,127.2,126.9 (q,J = 4 Hz,2C), 125.9, 124.5 (q, J = 271 Hz, 1C), 122.8 (q, J = 33 Hz, 1C), 115. 9, 78.6, 78.3, 59.22, 59.16, 55.2, 50.7, 38.5, 36.3.…”

“…11,12 Other approaches to azetidine-3-amines are based upon reductive amination. 8,13 Yet another synthesis of azetidine-3-amines, which has been used sporadically, is the direct displacement of an azetidine electrophile with an amine nucleophile. 14 This approach is more frequently encountered in the patent literature, 15 with a direct displacement of 1-benzhydrylazetidin-3-yl methanesulfonate 1 being the most frequently encountered azetidine electrophile.…”

Anti-inflammatory and anti-oxidative effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on β-amyloid-induced microglial activation

“…For instance, previous studies described the memory-restorative effect of ezetimibe—another well-known azetidine derivative—in memory dysfunctions associated with dementia of Alzheimer’s type, and discussed the potentially beneficial action of ezetimibe in suppressing plaque inflammation ( 7 ). The biological functions of azetidine derivatives against serotonin, norepinephrine, and dopamine transporters have also been reported ( 8 , 9 ). Recently, we described the protective effects of KHG26792—a novel azetidine derivative—on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in BV-2 cells and on hypoxia-induced toxicity through the suppression of microglial activation in BV-2 cells ( 10 , 11 ).…”