Antagonists of Orexin Receptors as Potential Treatment of Sleep Disorders, Obesity, Eating Disorders, and Other Neurological and Psychiatric Disorders Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:

Oxazole Orexin Receptor Antagonists

Patent Application Number:

US 2016/0176858 A1

Publication date:

23 June, 2016

Priority Application:


Priority date:

8 August, 2013


Liverton, N.; Beshore, D. C.; Kuduk, S. D.; Luo, Y.; Meng, N.; Yu, T.

Applicant: Disease Area:

Merck Sharp & Dohme Corp., Rahway, NJ, USA Neurological and psychiatric disorders and Biological Target:

Orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R)

other diseases in which orexin receptors are involved The invention in this patent application relates to oxazole derivatives represented generally by formula (I) and possess activities as antagonists of orexin receptors. These compounds may potentially be used for the treatment or prevention of neurological and


psychiatric disorders as well as other diseases in which the orexin receptors are involved. Orexin A (OX-A) and orexin B (OX-B), also named hypocretin-1 and hypocretin-2, respectively, are two neuropeptides produced in the hypothalamus. OX-A is a 33 amino acid peptide and OX-B is a 28 amino acid peptide, and the two polypeptides share 46% homology. Orexins stimulate food consumption in rats, a finding that suggests they play important physiological roles as mediators in the central feedback mechanism to regulate feeding behaviors. Orexins also regulate states of sleep and wakefulness. Therefore, their regulations can potentially provide novel therapies to treat narcoleptic or insomniac patients. In addition, they play roles in arousal, reward, learning, and memory. Researchers have identified two orexin receptors that can bind the orexin peptides known as orexin-1 receptor (OX1 or OX1R) and orexin-2 receptor (OX2 or OX2R). The two receptors belong to the G protein-coupled receptors super family and share 64% homology. OX1R displays higher selectivity toward binding to OX-A and shows about 10-fold higher affinity for OX-A than OX-B. However, OX2R displays almost equal affinities to both OX-A and OX-B. The orexin receptors are widely distributed throughout the brain, including brain regions involved in drug reward and addiction. They are also found to varying degrees in peripheral tissues, such as pituitary, adrenal, gonads, kidney, pancreas, heart, and lung. The orexins and their receptors are involved in multiple physiological processes such as the regulation of sleep/wakefulness states, energy homeostasis, and reward. These activities suggest that the orexins and their receptors are implicated in a variety of diseases. Orexin receptor antagonists such as the compounds described in this patent application could therefore potentially be useful for the treatment, prevention, amelioration, and controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors. These disorders include, but are not limited to, sleep disorders (including insonmia, sleep disturbances, improving quality of sleep, rapid eye movement (REM) sleep, and others), treating or controlling obesity, apatite, and eating disorder. The inventors mentioned a large list of disorders that can potentially be treated with orexin receptor antagonists. Important Compound Classes:

Received: August 17, 2016 Published: August 31, 2016 r 2016 American Chemical Society

876 | ACS Med. Chem. Lett. 2016, 7, 876–877

ACS Medicinal Chemistry Letters


Key Structures:

The inventors described the structures and synthesis of 77 compounds of formula (I) including the following representative examples:

Biological Assay:

The activities of the compounds of formula (I) as orexin receptor OX1R and/or OX2R antagonists were tested using well-known methodology including the FLIPR Ca2+ Flux Assay.

Biological Data:

The IC50 data obtained from testing the above representative examples are listed in the following table:

Recent Review Articles:

1. Kumar, A.; Chanana, P.; Choudhary, S. Pharmacol. Rep. 2016, 68 (2), 231 242. 2. Roecker, A. J.; Cox, C. D.; Coleman, P. J. J. Med. Chem. 2016, 59 (2), 504 530. 3. Xu, T.-R.; Yang, Y.; Ward, R.; Gao, L.; Liu, Y. Cell. Signal. 2013, 25 (12), 2413 2423.

’ AUTHOR INFORMATION Corresponding Author

*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail: [email protected] Notes

The author declares no competing financial interest.

877 |ACS Med. Chem. Lett. 2016, 7, 876–877

Antagonists of Orexin Receptors as Potential Treatment of Sleep Disorders, Obesity, Eating Disorders, and Other Neurological and Psychiatric Disorders.

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