IP Library › Granted Patent US 12,503,475
Granted Patent B2
US 12,503,475 · App. 18/024,216 · Granted Dec 23, 2025

Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists

Inventors: Bruce Lefker (Swampscott, MA); Karl Gibson (Sandwich, GB); Matthew Spendiff (Cambridge, GB); Paul Humphries (Santa Clara, CA); Sarah Bucknell (Cambridge, GB); Wojciech Zawodny (Cambridge, GB); Roderick Alan Porter (Hertfordshire, GB)
Assignee: CENTESSA PHARMACEUTICALS (UK) LIMITED
C07D487/10C07D209/54C07D221/20C07D403/06C07D405/06C07D405/14C07D413/06
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Quick Facts
Patent No.
US 12,503,475
App. No.
18/024,216
Granted
Dec 23, 2025
Kind
B2
Abstract

The present disclosure relates to compounds of Formula (I′): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating orexin receptor activity and may be used in the treatment of disorders in which orexin receptor activity is implicated, such as narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or a complication in emergence from anaesthesia.

Claims (47)

1 . A compound of Formula (I″):

or a pharmaceutically acceptable salt thereof, wherein:

X is —C(R X1 ) 3 , —OR X2 , or —N(R X2 ) 2 ;

Y is —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CF 2 —, —CH 2 —NH—, —NH—CH 2 —, —CH 2 —N(CH 2 CF 3 )—, or —N(CH 2 —CF 3 )—CH 2 —;

Z is —O— or —NR Z —;

each R X1 independently is H, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl,

or two R X1 together with the atom to which they are attached form a C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with oxo, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy,

or three R X1 together with the atom to which they are attached form a C 4 -C 10 cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;

each R X2 independently is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl,

or two R X2 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;

each R Z is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

Ar 1 is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R 3 ;

R 1 is —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)(C 3 -C 10 cycloalkyl), —S(C 1 -C 6 alkyl), —S(C 6 -C 10 aryl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 6 -C 10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C 3 -C 10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C 6 -C 10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 1S ;

each R 1S independently is oxo, halogen, —CN, —OH, —O—(CH 2 ) 2 —OC 1 —C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

R 2 is halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SH, —S(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), —S(C 6 -C 10 aryl), —SO 2 (C 6 -C 10 aryl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 6 -C 10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C 3 -C 10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C 6 -C 10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 2S ;

each R 2S independently is oxo, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R 3 independently is halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1-6 alkoxy;

R 4a is H, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1-6 alkoxy;

R 4b is H, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1-6 alkoxy; and

n is 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein Z is —NR Z ;

R Z is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

R 1 is —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 1S ; and

each R 1S independently is halogen, —CN, —OH, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl.

3 . The compound of claim 1 , wherein Z is —NH— and R 1 is —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 1S ; and

each R 1S independently is halogen, —CN, —OH, or C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl.

4 . The compound of claim 1 , wherein X is —C(R X1 ) 3 or —N(R X2 ) 2 , wherein

each R X1 independently is H, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy; or wherein two R X1 together with the atom to which they are attached form a C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy; and

each R X2 independently is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; or wherein two R X2 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

5 . The compound of claim 1 , wherein X is

6 . The compound of claim 1 , wherein Ar 1 is C 6 -aryl or 5- or 6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 3 .

7 . The compound of claim 1 , wherein R 1 is methyl, isopropyl, ethyl, —CF 3 , —CHF 2 , CH 2 F, —CF 2 CH 3 , —CF (CH 3 ) 2 , cyclopropyl, or fluorocyclopropyl.

8 . The compound of claim 1 , wherein R 2 is —CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 6 -C 10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C 3 -C 10 cycloalkyl), or —O-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 2S .

9 . The compound claim 1 , wherein R 2 is

10 . The compound claim 1 , wherein each R 2S independently is oxo, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkoxy.

11 . The compound of claim 1 , wherein each R 3 independently is halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .

12 . The compound of claim 1 , wherein each R 3 independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1-6 alkoxy.

13 . The compound of claim 1 , wherein R 4a is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; and R 4b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl.

14 . The compound of claim 1 , wherein n is 1 or 2.

15 . A compound selected from:

or a pharmaceutically acceptable salt of any one thereof.

16 . The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt of any one thereof.

17 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

18 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a neurological disorder, a symptom of a rare genetic disorder, a psychiatric disorder, a mental health disorder, a circadian rhythm disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or facilitating emergence from anesthesia.

19 . The method, of claim 18 , wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

20 . A method of treating narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or a complication in emergence from anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (9)
RELEASE OF SECURITY INTEREST Recorded Jun 24, 2026
From: OXFORD FINANCE LLC
To: CENTESSA PHARMACEUTICALS (UK) LIMITED
Reel/Frame 075069/0879 →
CHANGE OF NAME Recorded Jul 10, 2025
From: OREXIA THERAPEUTICS LIMITED
To: CENTESSA PHARMACEUTICALS (OREXIA) LIMITED
Reel/Frame 071665/0741 →
SECURITY INTEREST Recorded Dec 31, 2024
From: CENTESSA PHARMACEUTICALS (UK) LIMITED
To: OXFORD FINANCE LLC
Reel/Frame 069708/0039 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 20, 2023
From: OREXIA THERAPEUTICS LIMITED
To: CENTESSA PHARMACEUTICALS (UK) LIMITED
Reel/Frame 065300/0110 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2023
From: SPENDIFF, MATTHEW; BUCKNELL, SARAH; ZAWODNY, WOJCIECH
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 064721/0819 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2023
From: HUMPHRIES, PAUL
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 064721/0767 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2023
From: LEFKER, BRUCE
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 064721/0738 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2023
From: PORTER, RODERICK
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 064721/0849 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2023
From: GIBSON, KARL
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 064721/0781 →
Continuity (2)
Provisional Application 63074216 · Sep 3, 2020
Related Publication 20230271973A1 · Aug 31, 2023
References Cited (80)
US 4522811A · Eppstein et al. · 1985 [cited by applicant]
US 5763263A · Dehlinger · 1998 [cited by applicant]
US 8871794B2 · Yanagisawa · 2014 [cited by applicant]
US 20100074863A1 · Or et al. · 2010 [cited by applicant]
US 20200255403A1 · Bogen et al. · 2020 [cited by applicant]
US 20210155636A1 · Pennington et al. · 2021 [cited by applicant]
US 20230331720A1 · Lefker et al. · 2023 [cited by applicant]
US 20240239744A1 · Christopher · 2024 [cited by applicant]
US 20240360175A1 · O'Boyle et al. · 2024 [cited by applicant]
US 20250100968A1 · Ott et al. · 2025 [cited by applicant]
WO WO2008076415A1 · 2008 [cited by applicant]
WO WO2008128121A1 · 2008 [cited by applicant]
WO WO2009070689A1 · 2009 [cited by applicant]
WO WO2011006960A1 · 2011 [cited by applicant]
WO WO2011073376A1 · 2011 [cited by applicant]
WO WO2012117219A1 · 2012 [cited by applicant]
WO WO2013052845A1 · 2013 [cited by applicant]
WO WO2013092893A1 · 2013 [cited by applicant]
WO WO2015078949A1 · 2015 [cited by applicant]
WO WO2016021629A1 · 2016 [cited by applicant]
WO WO2016022464A1 · 2016 [cited by applicant]
WO WO2017135306A1 · 2017 [cited by applicant]
WO WO2018164191A1 · 2018 [cited by applicant]
WO WO2018164192A1 · 2018 [cited by applicant]
WO WO2019027058A1 · 2019 [cited by applicant]
WO WO2020004536A1 · 2020 [cited by applicant]
WO WO2020122092A1 · 2020 [cited by applicant]
WO WO2020122093A1 · 2020 [cited by applicant]
WO WO2020158958A1 · 2020 [cited by applicant]
WO WO2020167706A1 · 2020 [cited by applicant]
WO WO2021048821A1 · 2021 [cited by applicant]
WO WO2021048822A1 · 2021 [cited by applicant]
WO WO2021065893A1 · 2021 [cited by applicant]
WO WO2021107023A1 · 2021 [cited by applicant]
WO WO2021108628A1 · 2021 [cited by applicant]
WO WO2021137982A1 · 2021 [cited by applicant]
WO WO2022051583A1 · 2022 [cited by applicant]
WO WO2022051596A1 · 2022 [cited by applicant]
WO WO2022207935A1 · 2022 [cited by applicant]
WO WO2023017180A1 · 2023 [cited by applicant]
WO WO2023167865A1 · 2023 [cited by applicant]
WO WO2023167925A1 · 2023 [cited by applicant]
Chemical Abstracts Service. CAS Registry: 70693-62-8, PubChem SID: 117687804. ABBLIS Chemicals: pp. 1-5. STN Entry Date Apr. 12, 2011. Retrieved Nov. 7, 2024. Retrieved from: https://pubchem.ncbi.nlm.nih.gov/substance/1… [cited by applicant]
Li, Kangnan. et al. Diastereoselective and Enantiospecific Synthesis of 1,3-Diamines via 2-Azaallyl Anion Benzylic Ring-Opening of Aziridines. Organic Letters 19(16):4239-4242 (2017). [cited by applicant]
Tanaka, Kouichi. et al. Reductive Amination of Ketonic Compounds Catalyzed by Cp*Ir(III) Complexes Bearing a Picolinamidato Ligand. The Journal of Organic Chemistry 84(17):10962-10977 (2019). [cited by applicant]
Baykal, S. et al. Decreased serum orexin A levels in drug-naive children with attention deficit and hyperactivity disorder. Neurol Sci. Mar. 2019;40(3):593-602. doi: 10.1007/s10072-018-3692-8. Epub Jan. 7, 2019. [cited by applicant]
Black, S.W. et al. Challenges in the development of therapeutics for narcolepsy. Prog. Neurobiol., 2017; 152:89-113. [cited by applicant]
Boss, C. et. al. Orexin research: patent news from 2016. Expert Opinion on Therapeutic Patents, vol. 27, No. 10, Jun. 28, 2017, pp. 1123-1133. [cited by applicant]
Calva, C.B. et al. Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction. Brain Res. Mar. 15, 2020;1731:145921. doi: 10.1016/j.brainres.2018.08.024. Epu… [cited by applicant]
Cheong, R.Y. et al. The Role of Hypothalamic Pathology for Non-Motor Features of Huntington's Disease. J Huntingtons Dis. 2019;8(4):375-391. doi: 10.3233/JHD-190372. [cited by applicant]
Database STN, CAS, File Registry, RN 1422063-50-0, “Methanesulfonamide, N-[(2R,3S)-2-(phenylmethyl)-3-pyrrolidinyl]-, rel-” (CA Index Name), Supplier WuXi AppTec Co., Ltd. American Chemical Society, CAS; entered STN: Fe… [cited by applicant]
De Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. Jan. 1998;95:322-7. [cited by applicant]
Funato, H. et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. Jan. 7, 2009;9(1):64-76. doi: 10.1016/j.cmet.2008.10.010. [cited by applicant]
Hara, J. et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. May 2001;30(2):345-54. doi: 10.1016/s0896-6273(01)00293-8. [cited by applicant]
Hasegawa, E. et al. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest. Feb. 2014;124(2):604-16. doi: 10.1172/JCI71017. Epub Jan. 2, 2014. [cited by applicant]
Irukayama-Tomobe, Y. et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. PNAS, May 30, 2017;114(22):5731-6. [cited by applicant]
Kelz, M.B. et al. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A. Jan. 29, 2008;105(4):1309-14. doi: 10.1073/pnas.0707146105. Epub Jan. 14, 2008. [cited by applicant]
Liu, M.F. et al. Orexin-A Exerts Neuroprotective Effects via OX1R in Parkinson's Disease. Front Neurosci. Nov. 15, 2018;12:835. doi: 10.3389/fnins.2018.00835; 18 pages. [cited by applicant]
Mahoney, C.E, et al. The neurobiological basis of narcolepsy. Nat Rev Neurosci. Feb. 2019;20(2):83-93. doi: 10.1038/s41583-018-0097-x. [cited by applicant]
Mieda, M.et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. PNAS, Mar. 30, 2004;101:4649-54. [cited by applicant]
Mignot, E. et al. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci. Nov. 2002;5 Suppl:1071-5. doi: 10.1038/nn944. [cited by applicant]
Mignot, E. Narcolepsy: genetics, immunology, and pathophysiology. In: Kryger M, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017; Chapter 89, pp. 855-872.e7. [cited by applicant]
Mochizuki, T. et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A. Mar. 15, 2011;108(11):4471-6. doi: 10.1073/pnas.1012456108. Epub Feb. 28,… [cited by applicant]
Modi, H.R., et al. Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation. PLoS One. Sep. 28, 2017;12(9):e0182707. doi: 10.1371/journal.pone.0182707; 20 pa… [cited by applicant]
Nishino, S. et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. Jan. 1, 2000;355(9197):39-40. doi: 10.1016/S0140-6736(99)05582-8. [cited by applicant]
Pallais, J.P. et al. Orexin/hypocretinin in multiple sclerosis and experimental autoimmune encephalomyelitis. Neural Regen Res. Jun. 2020;15(6):1039-1040. doi: 10.4103/1673-5374.270310. [cited by applicant]
Patel, V.H. et al. Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection. Clin Sci (Lond). Dec. 13, 20183;132(24):2547-2564. doi: 10.1042/CS20180150. [cited by applicant]
Peyron, R. et al. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin. Oct. 2000;30(5):263-88. doi: 10.1016/s0987-7053(00)00227-6. [cited by applicant]
Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, Feb. 20, 1998;92:573-585. [cited by applicant]
Tabuchi, S. et al. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J. Neurosci., May 7, 2014;34(19):6495-6509. [cited by applicant]
Thannickal, T.C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. Sep. 2000;27(3):469-74. doi: 10.1016/s0896-6273(00)00058-1. [cited by applicant]
Thomasy, H.E. et al. Hypocretin Mediates Sleep and Wake Disturbances in a Mouse Model of Traumatic Brain Injury. J Neurotrauma. Mar. 1, 2019;36(5):802-814. doi: 10.1089/neu.2018.5810. Epub Oct. 3, 2018. [cited by applicant]
Um, Y.H. and Lim, H.K. Orexin and Alzheimer's Disease: A New Perspective. Psychiatry Investig. Jul. 2020;17(7):621-626. doi: 10.30773/pi.2020.0136. Epub Jun. 11, 2020. [cited by applicant]
Wei, W, et al. Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action. Cell Metab. Jun. 3, 2014;19(6):927-40. doi: 10.1016/j.cmet.2014.03.016. Epub May 1, 20… [cited by applicant]
Yukitake, H. et al. TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice. Pharmacol Biochem Behav, 2019;187:172794, 10 pages. [cited by applicant]
PCT/EP2022/058817 International Search Report and Written Opinion dated Aug. 3, 2022. [cited by applicant]
PCT/US2021/049003 International Search Report and Written Opinion dated Nov. 11, 2021. [cited by applicant]
PCT/US2021/049021 International Search Report and Written Opinion dated Nov. 11, 2021. [cited by applicant]
PCT/US2023/014139 International Search Report and Written Opinion dated May 30, 2023. [cited by applicant]
PCT/US2023/014275 International Search Report and Written Opinion dated Jun. 15, 2023. [cited by applicant]