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Sleep Initiation and Maintenance Disorders: HELP
Articles by Anthony L. Gotter
Based on 10 articles published since 2009
(Why 10 articles?)
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Between 2009 and 2019, Anthony L. Gotter wrote the following 10 articles about Sleep Initiation and Maintenance Disorders.
 
+ Citations + Abstracts
1 Review The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia. 2017

Coleman, Paul J / Gotter, Anthony L / Herring, W Joseph / Winrow, Christopher J / Renger, John J. ·Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486; email: paul_coleman@merck.com. · Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486. · Department of Clinical Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486. ·Annu Rev Pharmacol Toxicol · Pubmed #27860547.

ABSTRACT: Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA

2 Review International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. 2012

Gotter, Anthony L / Webber, Andrea L / Coleman, Paul J / Renger, John J / Winrow, Christopher J. ·Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004. christopher_winrow@merck.com. ·Pharmacol Rev · Pubmed #22759794.

ABSTRACT: Orexin signaling is essential for normal regulation of arousal and behavioral state control and represents an attractive target for therapeutics combating insomnia. Alternatively termed hypocretins, these neuropeptides were named to reflect sequence similarity to incretins and their potential to promote feeding. Current nomenclature reflects these molecular and biochemical discovery approaches in which HCRT, HCRTR1, and HCRTR2 genes encode prepro-orexin, the orexin 1 receptor (OX(1)) and the orexin 2 receptor (OX(2))-gene names designated by the Human Genome Organization and receptor names designated by the International Union of Basic and Clinical Pharmacology. Orexinergic neurons are most active during wakefulness and fall silent during inactive periods, a prolonged disruption in signaling most profoundly resulting in hypersomnia and narcolepsy. Hcrtr2 mutations underlie the etiology of canine narcolepsy, deficiencies in orexin-producing neurons are observed in the human disorder, and ablation of mouse orexin neurons or the Hcrt gene results in a narcolepsy-cataplexy phenotype. The development of orexin receptor antagonists and genetic models targeting components of the orexin pathway have elucidated the OX(2) receptor-specific role in histamine-mediated arousal and the contribution of both receptors in brainstem pathways involved in vigilance state gating. Orexin receptor antagonists of varying specificity uncovered additional roles beyond sleep and feeding that include addiction, depression, anxiety, and potential influences on peripheral physiology. Combined genetic and pharmacological approaches indicate that orexin signaling may represent a confluence of sleep, feeding, and reward pathways. Selective orexin receptor antagonism takes advantage of these properties toward the development of novel insomnia therapeutics.

3 Article The dual orexin receptor antagonist, DORA-22, lowers histamine levels in the lateral hypothalamus and prefrontal cortex without lowering hippocampal acetylcholine. 2017

Yao, Lihang / Ramirez, Andres D / Roecker, Anthony J / Fox, Steven V / Uslaner, Jason M / Smith, Sean M / Hodgson, Robert / Coleman, Paul J / Renger, John J / Winrow, Christopher J / Gotter, Anthony L. ·Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA. · Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA. · Department of In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA. ·J Neurochem · Pubmed #28444767.

ABSTRACT: Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)

4 Article Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties. 2015

Kuduk, Scott D / Skudlarek, Jason W / DiMarco, Christina N / Bruno, Joseph G / Pausch, Mark H / O'Brien, Julie A / Cabalu, Tamara D / Stevens, Joanne / Brunner, Joseph / Tannenbaum, Pamela L / Garson, Susan L / Savitz, Alan T / Harrell, Charles M / Gotter, Anthony L / Winrow, Christopher J / Renger, John J / Coleman, Paul J. ·Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: skuduk@noviratherapeutics.com. · Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. · Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA. · Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. · Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. ·Bioorg Med Chem Lett · Pubmed #25981685.

ABSTRACT: Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

5 Article Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements. 2015

Roecker, Anthony J / Mercer, Swati P / Bergman, Jeffrey M / Gilbert, Kevin F / Kuduk, Scott D / Harrell, C Meacham / Garson, Susan L / Fox, Steven V / Gotter, Anthony L / Tannenbaum, Pamela L / Prueksaritanont, Thomayant / Cabalu, Tamara D / Cui, Donghui / Lemaire, Wei / Winrow, Christopher J / Renger, John J / Coleman, Paul J. ·Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com. · Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. ·Bioorg Med Chem Lett · Pubmed #25613676.

ABSTRACT: Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.

6 Article Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. 2014

Roecker, Anthony J / Reger, Thomas S / Mattern, M Christa / Mercer, Swati P / Bergman, Jeffrey M / Schreier, John D / Cube, Rowena V / Cox, Christopher D / Li, Dansu / Lemaire, Wei / Bruno, Joseph G / Harrell, C Meacham / Garson, Susan L / Gotter, Anthony L / Fox, Steven V / Stevens, Joanne / Tannenbaum, Pamela L / Prueksaritanont, Thomayant / Cabalu, Tamara D / Cui, Donghui / Stellabott, Joyce / Hartman, George D / Young, Steven D / Winrow, Christopher J / Renger, John J / Coleman, Paul J. ·Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com. · Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: treger@gtweed.com. · Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. · Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. · Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. · Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. · Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. · Department of Basic Pharmaceutical Sciences, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. ·Bioorg Med Chem Lett · Pubmed #25248679.

ABSTRACT: Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.

7 Article Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis. 2014

Roecker, Anthony J / Mercer, Swati P / Harrell, C Meacham / Garson, Susan L / Fox, Steven V / Gotter, Anthony L / Prueksaritanont, Thomayant / Cabalu, Tamara D / Cui, Donghui / Lemaire, Wei / Winrow, Christopher J / Renger, John J / Coleman, Paul J. ·Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com. · Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. · Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. ·Bioorg Med Chem Lett · Pubmed #24704030.

ABSTRACT: Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.

8 Article Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. 2014

Roecker, Anthony J / Mercer, Swati P / Schreier, John D / Cox, Christopher D / Fraley, Mark E / Steen, Justin T / Lemaire, Wei / Bruno, Joseph G / Harrell, C Meacham / Garson, Susan L / Gotter, Anthony L / Fox, Steven V / Stevens, Joanne / Tannenbaum, Pamela L / Prueksaritanont, Thomayant / Cabalu, Tamara D / Cui, Donghui / Stellabott, Joyce / Hartman, George D / Young, Steven D / Winrow, Christopher J / Renger, John J / Coleman, Paul J. ·Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486 (USA). anthony_roecker@merck.com. ·ChemMedChem · Pubmed #24376006.

ABSTRACT: The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.

9 Article Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties. 2012

Coleman, Paul J / Schreier, John D / Cox, Christopher D / Breslin, Michael J / Whitman, David B / Bogusky, Michael J / McGaughey, Georgia B / Bednar, Rodney A / Lemaire, Wei / Doran, Scott M / Fox, Steven V / Garson, Susan L / Gotter, Anthony L / Harrell, C Meacham / Reiss, Duane R / Cabalu, Tamara D / Cui, Donghui / Prueksaritanont, Thomayant / Stevens, Joanne / Tannenbaum, Pamela L / Ball, Richard G / Stellabott, Joyce / Young, Steven D / Hartman, George D / Winrow, Christopher J / Renger, John J. ·Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com ·ChemMedChem · Pubmed #22307992.

ABSTRACT: Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.

10 Article Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia. 2012

Winrow, Christopher J / Gotter, Anthony L / Cox, Christopher D / Tannenbaum, Pamela L / Garson, Susan L / Doran, Scott M / Breslin, Michael J / Schreier, John D / Fox, Steven V / Harrell, Charles M / Stevens, Joanne / Reiss, Duane R / Cui, Donghui / Coleman, Paul J / Renger, John J. ·Neuroscience Department, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. christopher_winrow@merck.com ·Neuropharmacology · Pubmed #22019562.

ABSTRACT: Orexin (hypocretin) neuropeptides promote wakefulness by signaling through two G-protein coupled receptors, Orexin 1 Receptor (OX(1)R) and Orexin 2 Receptor (OX(2)R). MK-6096 is an orally bioavailable potent and selective reversible antagonist of OX(1)R and OX(2)R currently in clinical development for insomnia. In radioligand binding and functional cell based assays MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel of >170 receptors and enzymes. MK-6096 occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM, and dose-dependently reduced locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). DORA-22, an analog of MK-6096, exhibits similar sleep promoting properties that are absent OX(1/2)R double knockouts, demonstrating the mechanism of action and specificity of these effects. These findings with a novel, structurally distinct class of OxR antagonists provide further validation of the orexin pathway as an effective target to promote normal sleep. Comparative analysis of the biochemical and pharmacokinetic properties of these compounds relative to other OXR antagonists provides a basis for understanding the attributes critical for in vivo efficacy. This mechanism is distinct from current standard of care such that MK-6096 represents a novel and selective therapeutic for the treatment of insomnia. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.