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

Abstract

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...

Discovery of Novel Selective Norepinephrine Reuptake Inhibitors: 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231)

“…Compound S-17b was selected based on its in vitro profile for complete in vivo characterization. 18 Table 4 highlights the male, intact female, and ovariectomized female (OVX) rat pharmacokinetic parameters of S-17b using both intravenous and oral administration. In general, S-17b showed high to moderate clearance, high volume of distribution, and long terminal half-life.…”

Discovery of Novel Selective Norepinephrine Inhibitors: 1-(2-Morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-Dioxides (WYE-114152)

“…Compound 10b was selected based on its in vitro profile for in vivo characterization . Table highlights the pharmacokinetic parameters of 10b in the male rat using both intravenous and oral administration.…”