Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an <i>N</i>,<i>N</i>‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats

Whitman, David B.; Cox, Christopher D.; Breslin, Michael J.; Brashear, Karen M.; Schreier, John D.; Bogusky, Michael J.; Bednar, Rodney A.; Lemaire, Wei; Bruno, Joseph G.; Hartman, George D.; Reiss, Duane R.; Harrell, C. Meacham; Kraus, Richard L.; Li, Yuxing; Garson, Susan L.; Doran, Scott M.; Prueksaritanont, Thomayant; Li, Chunze; Winrow, Christopher J.; Koblan, Kenneth S.; Renger, John J.; Coleman, Paul J.

doi:10.1002/cmdc.200900069

Cited by 71 publications

(46 citation statements)

References 12 publications

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“…The diazepane compound MK 4305 (33) with K i values of 0.55 and 0.35 nM at OX1-R and OX2-R [49,180,184] as well as a molecular weight of 450.19 g/mol has a log P of 4.24 and is included in a clinical phase III study. A volume distribution of 2.6 (rat) and 0.8 l/kg b. wt (dog) lets expect rather modest lipophilic properties.…”

Section: Non-peptide Ox-r Ligandsmentioning

confidence: 99%

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Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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Section: Non-peptide Ox-r Ligandsmentioning

confidence: 99%

“…A volume distribution of 2.6 (rat) and 0.8 l/kg b. wt (dog) lets expect rather modest lipophilic properties. MK 4305 has been developed using 7-methyldiazepane and triazolyl-benzamide as core unit and is only one in a series of diazepanes highly potent as DORAs (see (34), (35) (Figure 7) [49,184].…”

Section: Non-peptide Ox-r Ligandsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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“…This evidence therefore precludes the use of sleep-inducing agents under operational conditions in which individuals might be called upon to perform without impairment after taking the (13)(14)(15), impaired concentration and attention (16)(17)(18)(19), increased risk for accidents and injuries (20,21), worsened quality of life (22), increased aggression (23)(24)(25)(26), and increased use of alcohol (27,28). Several studies have also demonstrated that disturbed sleep is a potent risk factor for later onset development of major depression, panic disorder, alcohol, and substance abuse (27)(28)(29)(30). Therefore, an effective treatment for sleep disturbances that can be safely utilized in deployed military personnel in combat operations without performance-impairing effects has the potential for improving the success of combat operations, inoculating soldiers against battlefield stress-related psychiatric illnesses, and preserving the psychological health of the soldiers throughout the full deployment lifecycle.…”

Section: Rationalementioning

confidence: 99%

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

Neylan¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER During Year 3, revisions were made to the protocol, informed consent, and HIPAA documents to allow for additional data collection during the hospital portion of the study via actigraphy. Recruitment materials were also revised in order to target a non-smoking population. This greatly reduced the amount of participants ruled out during the phone screening process, improving phone screening success. Safety reports continue to be sent to Actelion on a monthly basis. Both blinded and unblinded monitoring visits of study procedures and facilities are ongoing. Throughout Year 3, many new study team members were hired and trained (Study Coordinator, Recruiter, Research Assistant, and Lab Manager). The study team also expanded to include additional informed consent administrators, clinical interviewers, as well as sleep technicians and neuropsychological assessment administrators in order to reach the new quarterly enrollment goal of 39 participants. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTEnrollment is expected to increase throughout Year 4 due to the actions taken above.Neurocognitive Performance, Sleep, Hypocretin, Orexin 100 ANNUAL PROGRESS REPORT September 28, 2012Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance USAMRMC Grant W81XWH-09-2-0080 Thomas Neylan, M.D., Principal Investigator INTRODUCTIONAn integrated translational study will be conducted to examine the effect of a novel hypocretin/orexin antagonist, almorexant (ALM), compared to a standard hypnotic, zolpidem (ZOL), and placebo (PBO) on neurocognitive performance at peak concentration post dosing. The human study compone...

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“…Therefore, more effective hypnotics are needed that facilitate sleep that is easily reversible in the event of an unexpected awakening that demands unimpaired cognitive and psychomotor performance. Recently, antagonism of the hypocretin (Hcrt; also called orexin) receptors has been identified as a target mechanism for the next generation of sleep medications (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Whitman et al, 2009;Hoever et al, 2010Hoever et al, , 2012aColeman et al, 2012;Herring et al, 2012;Winrow et al, 2012;Betschart et al, 2013). The Hcrt system is well known to play an important role in the maintenance of wakefulness (de Lecea, 2012;Inutsuka and Yamanaka, 2013;Mieda and Sakurai, 2013;Saper, 2013).…”

Section: Introductionmentioning

confidence: 99%

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Kilduff¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)September 2014 (From -To) REPORT TYPE Annual DATES COVERED P ERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SRI InternationalMenlo Park, CA 94025-3493 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT SUPPLEMENTARY NOTES ABSTRACTDuring Year 5, we continued tests of the hypothesis that disfacilitation of wake-promoting systems by the hypocretin (Hcrt) receptor antagonist almorexant (ALM) results in less functional impairment than the inhibition of neural activity produced by the benzodiazepine receptor agonist zolpidem (ZOL). One paper was published (Morairty et al. 2014), another has been accepted for publication (Dittrich et al., in press) and a third is in resubmission (Vazquez-DeRose et al., submitted). Data collection for Aims 2c and 3b.2 have been completed and data analysis ongoing; manuscripts will be written and submitted during Year 6. Data collection and analysis of Aim 3a is nearing completion; an abstract summarizing this work has been submitted for presentation at the 2014 Society for Neuroscience meeting. Data collection for Aims 3b.3, 4c and 6a have been initiated. The overall results obtained to date are consistent with the hypothesis that the hypocretin/orexin antagonist ALM produces less functional impairment than the benzodiazepine receptor agonist zolpidem (ZOL) because ZOL causes a general inhibition of neural activity whereas ALM specifically disfacilitates wake-promoting systems. SUBJECT TERMSSleep, performance, drug, neurotransmitter, hypocretin, orexin, benzodiazepine, zolpidem, neurochemistry, microdialysis INTRODUCTIONAlmorexant (ALM) is a hypocretin/orexin (Hcrt) receptor antagonist with a novel mechanism of action that has shown promise as an effective hypnotic. Preclinical data demonstrate that animals treated with ALM are easily aroused from sleep and are free of ataxia and other behavioral impairments. If this observation is confirmed in humans, it would have enormous implications for the management of disturbed sleep in both military a...

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Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats

Cited by 71 publications

References 12 publications

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

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