4-Fluorosulfonylpiperidines: Selective 5-HT2A ligands for the treatment of insomnia

Fish, L. Rebecca; Gilligan, Myra; Humphries, Alexander C.; Ivarsson, Magnus; Ladduwahetty, T.; Merchant, Kevin J.; O’Connor, Desmond; Patel, Smita S.; Philipps, E.; Vargas, Hugo M.; Hutson, Peter H.; MacLeod, Angus M.

doi:10.1016/j.bmcl.2005.05.104

Cited by 41 publications

(27 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, nelotanserin treatment increased total NREM sleep time and deep sleep, the latter marked by increases in EEG delta power. These findings are in agreement with previously published reports of the effects of selective 5-HT 2A inverse agonists on rat sleep consolidation and delta power (Fish et al, 2005;Monti and Jantos, 2006;Morairty et al, 2008).…”

Section: Discussionsupporting

confidence: 93%

“…For example, eplivanserin, a selective 5-HT 2A inverse agonist, increases SWS and slow-wave EEG activity in humans and rats (Landolt et al, 1999;Francon et al, 2007). Likewise, volinanserin showed a dose-dependent increase in sleep consolidation characterized by a decrease in the number of NREM sleep bouts and concomitant increase in NREM sleepbout length (Fish et al, 2005;Morairty et al, 2008).…”

mentioning

confidence: 93%

“…Unlike 5-HT 2B receptors, which have limited CNS expression, 5-HT 2A and 5-HT 2C receptors are widely distributed in the CNS in areas that are implicated in the regulation of sleep and waking (Leysen, 2004). There is compelling preclinical and clinical evidence that supports a role for 5-HT 2A antagonism in the treatment of sleep maintenance insomnias (Borbély et al, 1988;Landolt et al, 1999;Fish et al, 2005;Popa et al, 2005;Monti and Jantos, 2006). Indeed, several selective 5-HT 2A inverse agonists have entered clinical development for the treatment of insomnia; these include eplivanserin, volinanserin, pruvanserin, and nelotanserin (Teegarden et al, 2008).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Al-Shamma¹,

Anderson²,

Chuang³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

5-Hydroxytryptamine (5-HT) 2A receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT 2A inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT 2A receptor with at least 30-and 5000-fold selectivity compared with 5-HT 2C and 5-HT 2B receptors, respectively. Nelotanserin dosed orally prevented (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT 2A agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.Serotonin has long been implicated in the regulation of sleep and wakefulness. Central serotonergic neurons of the dorsal raphe nucleus form part of the reticular activating system that innervates cortical and subcortical regions of the forebrain. As its name implies, this system modulates arousal in the central nervous system (CNS) and regulates sleep/wake states (Abrams et al., 2005). Within this system, 5-HT neurons are active during wakefulness, less active during nonrapid eye movement (NREM) sleep, and inactive during rapid eye movement (REM) sleep.5-HT activity in the CNS is mediated by multiple receptor subtypes that are classified into seven subfamilies (5-HT 1 to 5-HT 7 ) (Hoyer et al., 1994). The 5-HT 2 subfamily includes three subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C . Unlike 5-HT 2B receptors, which have limited CNS expression, 5-HT 2A and 5-HT 2C receptors are widely distributed in the CNS in areas that are implicated in the regulation of sleep and waking (Leysen, 2004). There is compelling preclinical and clinical evidence that supports a role for 5-HT 2A antagonism in the treatment of sleep maintenance insomnias (Borbély et al., This work was supported by Arena Phar...

show abstract

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 93%

mentioning

confidence: 99%

See 1 more Smart Citation

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Al-Shamma¹,

Anderson²,

Chuang³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…No acute gastrointestinal toxicity was seen in dogs following administration of a 10 mg/kg dose. Compound 4 was also evaluated in an anesthetized cardiovascular dog model [41]. Rising cumulative doses of 1, 3, 10 and 30 mg/kg were administered by IV infusion over 10 min followed by a 20-min evaluation period.…”

Section: Improvements In Pharmacokinetic Pro-perties: the Fused Pipermentioning

confidence: 99%

Discovery of JANUVIA™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.

Thornberry¹,

Weber²

2007

CTMC

188

110

View full text Add to dashboard Cite

The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an alpha-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective beta-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.

show abstract

“…In particular, substantial evidence supports 5-HT 2A receptor antagonists for preventing the development of behavioral and physiological changes associated with anxiety disorders , suggesting that these antagonists are promising preventive agents in the fight against stress-associated disorders. Several novel, more selective 5-HT 2A antagonists have recently been developed (Bartoszyk et al, 2003) and have been entered into clinical trials for treatments of schizophrenia and insomnia (de Paulis, 2001;Fish et al, 2005). These drugs appear to be well tolerated by all study participants (David et al, 2004) and thus should also be entered into trials for anxiety disorders, especially PTSD.…”

Section: Pharmacotherapy For Anxiety Disordersmentioning

confidence: 99%

Pharmacology of 5-HT2 Modulation of Amygdala & Hypothalamus in Anxiety Disorders

Jiang¹,

Chen²,

Smerin³

et al. 2011

Anxiety Disorders

View full text Add to dashboard Cite

4-Fluorosulfonylpiperidines: Selective 5-HT2A ligands for the treatment of insomnia

Cited by 41 publications

References 12 publications

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Discovery of JANUVIA™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.

Pharmacology of 5-HT2 Modulation of Amygdala & Hypothalamus in Anxiety Disorders

Contact Info

Product

Resources

About

4-Fluorosulfonylpiperidines: Selective 5-HT2A ligands for the treatment of insomnia

Cited by 41 publications

References 12 publications

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Discovery of JANUVIA&#8482; (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.

Pharmacology of 5-HT2 Modulation of Amygdala & Hypothalamus in Anxiety Disorders

Contact Info

Product

Resources

About

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Discovery of JANUVIA™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.