Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

Mahaney, Paige E.; Gavrin, Lori Krim; Trybulski, Eugene J.; Stack, Gary; Vu, A. T.; Cohn, Stephen T.; Ye, Fei; Belardi, Justin K.; Santilli, Arthur A.; Sabatucci, Joseph P.; Leiter, Jennifer; Johnston, Grace H.; Bray, Jeffrey D.; Burroughs, Kevin D.; Cosmi, Scott; Leventhal, Liza; Koury, Elizabeth J.; Zhang, Yingru; Mugford, Cheryl A.; Ho, Douglas M.; Rosenzweig‐Lipson, Sharon; Platt, Brian J.; Smith, Valerie A.; Deecher, Darlene C.

doi:10.1021/jm8002262

Cited by 21 publications

(34 citation statements)

References 22 publications

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“…The profiles appear to be correlated with the ClogP values. Linker extension (13) decreased the inhibitory activity, suggesting that the length of the linker is critical, especially for the NET inhibition. Next, substituents on benzene ring were evaluated to investigate the effects on selectivity against SERT and DAT.…”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

Fujimori

Yukawa

Kamei

et al. 2015

Bioorganic & Medicinal Chemistry

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Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

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Section: Resultsmentioning

confidence: 99%

“…Next, substituents on benzene ring were evaluated to investigate the effects on selectivity against SERT and DAT. 13 Replacement of the chlorine atom at the 3-position on benzene ring with fluorine (14) retained high selectivity. Meanwhile, similar exchange at the 4-position (15) decreased the selectivity.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

Fujimori

Yukawa

Kamei

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Mahaney et al .,[77] discovered a series of piperazine-containing analogues for norepinephrine reuptake inhibitors (NRIs) in animal models. On the basis of substitution pattern and animal testing profile, compound (68) (S)-(-)-(WAY-256805) was found to be a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM and Ki = 50 nM) and showed excellent selectivity over both the serotonin and dopamine transporters.…”

Section: Piperidinementioning

confidence: 99%

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

et al. 2011

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Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression.

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“…Compound 13 was determined to be a potent NRI with a minimum efficacious dose (MED) of 5 mg/kg in this in vivo model of thermoregulation. 14 In summary, we have reduced the metabolic liability of our earlier lead candidate 1 by replacing the methyl piperazine moiety with the more sterically demanding (cis)-3,5-dimethyl piperazine moiety to afford 13 (WAY-260022, NRI-022). The increased microsomal stability and lipophilicity of 13 pubs.acs.org/acsmedchemlett likely contribute to the good brain to plasma ratio of this compound.…”

mentioning

confidence: 97%

“…Toward this end, compounds were prepared, in an analogous fashion to the previously reported synthesis, 14 in an attempt to prevent the formation of nonefficacious compound 2. N-substituted piperazines, C-substituted piperazines, and 4-aminopiperidines, along with other analogues, were synthesized in this effort.…”

mentioning

confidence: 99%

Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter

Gavrin

Mahaney

Jenkins

et al. 2010

ACS Med. Chem. Lett.

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The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.KEYWORDS WAY-260022, norepinephrine reuptake inhibitor, serotonin transporter, dopamine transporter, brain penetration, vasomotor symptoms V asomotor symptoms (VMS) consist of hot flushes and night sweats due to hormonal fluctuations associated with menopause, peri-menopause, androgen decline, 1 or hormone deprivation resulting from treatments for prostate cancer. 2 Hot flushes are transient episodes ranging from a warming sensation to intense heat on the upper body and face, redness, and perspiration, often followed by chills. Hot flushes can occur frequently and unpredictably throughout the day and can last up to 30 min per flush. Night sweats are hot flushes with drenching perspiration that occur during the night, often disrupting sleep. VMS in menopausal women can begin as early as age 35 and in some cases can persist past the age of 70. 3 Patients who experience VMS say these episodes disrupt daily life and impact functional ability. In fact, VMS is the main complaint for which women seek medical treatment during menopause. 4 To date, the most prescribed and effective treatments for alleviating VMS are hormone replacement therapies (HRTs), including estrogens and/or progestins. However, hormone-based drugs are not appropriate for all patients 2 and are not recommended for women or men at risk for hormonally sensitive cancers. 5 The number of postmenopausal women, which is expected to increase from 470 million in 1990 to 1.23 billion by 2030, 6 and the decline in popularity of HRT 7 have intensified the need for new and improved treatments for VMS.The clear unmet medical need for nonhormonal therapies to relieve VMS has prompted significant research over the past few years. 8 It is widely known that estrogens modulate serotonin (5-HT) and norepinephrine (NE), two neurotransmitters that play a key role in thermoregulation. As fluctuating estrogen levels drop, 5-HT and NE levels become imbalanced and can result in thermoregulatory dysfunction leading to hot flushes and night sweats. 9 These biochemical findings prompted the clinical evaluation of dual 5-HT and NE reuptake inhibitors, such as fluoxetine, 10 venlafaxine, 11 and paroxetine 12 for the treatment of thermoregulatory dysfunction. These agents have shown modest clinical efficacy in reducing the frequency and severity of hot flushes.Because NE alone has been shown to stimulate the hypothalamus, which plays an important role in temperature regulation, 13 efforts within our laboratories have focused on identifying selective norepinephrine reuptake in...

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Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

Cited by 21 publications

References 22 publications

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter

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