IP Library › Granted Patent US 12,441,710
Granted Patent B2
US 12,441,710 · App. 18/230,329 · Granted Oct 14, 2025

Substituted piperidino compounds and related methods of treatment

Inventors: Lewis D. Pennington (Arlington, MA); Younggi Choi (Stow, MA); Hoan Huynh (Waltham, MA); Brian M. Aquila (Marlborough, MA); Ingo Andreas Mugge (Waltham, MA); Yuan Hu (Waltham, MA); James R. Woods (Waltham, MA); Brian Kenneth Raymer (Holliston, MA); Jörg Martin Bentzien (White Plains, NY); Jonathan Ward Lehmann (Burlington, MA); Srinivasa Karra (Pembroke, MA); Roman A. Valiulin (Cambridge, MA); Daljit Matharu (Lexington, MA)
Assignee: Alkermes, Inc.
C07D401/14A61P25/26C07D211/98C07D401/04C07D471/04C07D487/04
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,441,710
App. No.
18/230,329
Granted
Oct 14, 2025
Kind
B2
Abstract

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Claims (69)

1. A compound of Formula I-A or a pharmaceutically acceptable salt thereof:

wherein:

T is CR 6 or N;

U is CR 5 or N;

V is CR 4 or N;

W is CR 3 or N;

X is CR 2 or N;

and provided that

includes no more than 3 nitrogen atoms in the ring;

E is selected from the group consisting of NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, and C 1 -C 3 alkylene-(4 to 10-membered heterocyclyl) wherein the C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 -C 3 alkylene-(4 to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;

R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;

R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

R c and R d are each, independently, H, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

n is 0 or 1;

each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, halogen, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

or, alternatively, R 8 and R 11 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

or, alternatively, R 9 and R 10 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

p is 0, 1, 2, 3, or 4; and

each R 14 is, independently, selected from the group consisting of deuterium, halogen, hydroxyl, and cyano.

2. The compound of claim 1 , wherein

is selected from the group consisting of:

3. The compound of claim 1 , wherein

is selected from the group consisting of:

4. The compound of claim 1 , wherein

is selected from the group consisting of:

5. The compound of claim 1 , wherein

6. The compound of claim 1 , wherein p is 0.

7. The compound of claim 1 , wherein p is 1 or 2.

8. The compound of claim 1 , wherein E is NR a R b .

9. The compound of claim 1 , wherein E is C 1 -C 3 alkylene-NR a R b .

10. The compound of claim 1 , wherein E is unsubstituted C 1 -C 3 alkyl, unsubstituted C 2 -C 4 alkenyl, or unsubstituted C 2 -C 4 alkynyl.

11. The compound of claim 1 , wherein E is C 1 -C 3 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

12. The compound of claim 1 , wherein E is unsubstituted C 1 -C 3 alkyl.

13. The compound of claim 1 , wherein E is C 1 -C 3 alkyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

14. The compound of claim 1 , wherein E is unsubstituted C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, unsubstituted C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), substituted C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), unsubstituted 4- to 10-membered heterocyclyl, substituted 4- to 10-membered heterocyclyl, unsubstituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), or substituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl).

15. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted.

16. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

17. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 0.

18. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

19. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 1.

20. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.

21. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is unsubstituted.

22. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

23. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is unsubstituted and further wherein n is 0.

24. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

25. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted, (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium, (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted and further wherein n is 0, or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

26. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.

27. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

28. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.

29. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

30. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.

31. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

32. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.

33. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

34. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

35. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

36. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

37. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

38. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

39. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

40. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 7-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is independently H, unsubstituted C 1 -C 3 alkyl, or fluorine.

41. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

42. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

43. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

44. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(C 6 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is independently H, unsubstituted C 1 -C 3 alkyl, or fluorine.

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

46. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 45 .

47. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 45 .

Assignments (5)
SECURITY INTEREST Recorded Feb 13, 2026
From: ALKERMES, INC.
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 073790/0950 →
RELEASE OF SECURITY INTEREST IN PATENTS PREVIOUSLY RECORDED AT REEL/FRAME (072656/0509) Recorded Feb 13, 2026
From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT
To: ALKERMES, INC.
Reel/Frame 074858/0481 →
SECURITY INTEREST Recorded Oct 23, 2025
From: ALKERMES, INC.
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 072656/0509 →
RELEASE OF PATENT SECURITY AGREEMENTS Recorded Dec 24, 2024
From: MORGAN STANLEY SENIOR FUNDING, INC.
To: ALKERMES, INC.
Reel/Frame 069771/0616 →
SECURITY INTEREST Recorded Jun 14, 2024
From: ALKERMES, INC.
To: MORGAN STANLEY SENIOR FUNDING, INC.
Reel/Frame 067726/0001 →
Continuity (3)
Continuation 17556295 · Dec 20, 2021
Provisional Application 63128511 · Dec 21, 2020
Related Publication 20240076283A1 · Mar 7, 2024
References Cited (202)
US 5635599A · Pastan et al. · 1997 [cited by applicant]
US 6428985B1 · Bromberg et al. · 2002 [cited by applicant]
US 6492492B1 · Stayton et al. · 2002 [cited by applicant]
US 6808902B1 · Treuheit et al. · 2004 [cited by applicant]
US 7211253B1 · Way · 2007 [cited by applicant]
US 7271149B2 · Glaesner et al. · 2007 [cited by applicant]
US 7696322B2 · Bleck et al. · 2010 [cited by applicant]
US 7829679B2 · Ushida et al. · 2010 [cited by applicant]
US 7928074B2 · Khare · 2011 [cited by applicant]
US 8063182B1 · Brockhaus et al. · 2011 [cited by applicant]
US 8163522B1 · Brockhaus et al. · 2012 [cited by applicant]
US 8258163B2 · Yanagisawa et al. · 2012 [cited by applicant]
US 8765669B2 · Kajihara et al. · 2014 [cited by applicant]
US 8933197B2 · Stemmer et al. · 2015 [cited by applicant]
US 9527807B2 · Fukumoto et al. · 2016 [cited by applicant]
US 9611262B2 · Shireman et al. · 2017 [cited by applicant]
US 9815787B2 · Nagase et al. · 2017 [cited by applicant]
US 10017481B2 · Obrecht et al. · 2018 [cited by applicant]
US 10287305B2 · Fujimoto et al. · 2019 [cited by applicant]
US 10351522B2 · Nagase et al. · 2019 [cited by applicant]
US 10377770B2 · Aversa et al. · 2019 [cited by applicant]
US 10428023B2 · Kajita et al. · 2019 [cited by applicant]
US 10508083B2 · Fujimoto et al. · 2019 [cited by applicant]
US 10584097B2 · Kajita et al. · 2020 [cited by applicant]
US 10898737B2 · Fujimoto et al. · 2021 [cited by applicant]
US 11472805B2 · Chappie et al. · 2022 [cited by applicant]
US 11479552B2 · Yoshida et al. · 2022 [cited by applicant]
US 11760747B2 · Pennington · 2023 [cited by examiner]
US 20020127227A1 · Holmes et al. · 2002 [cited by applicant]
US 20020159969A1 · Agrawal et al. · 2002 [cited by applicant]
US 20030073822A1 · Lofling et al. · 2003 [cited by applicant]
US 20030229226A1 · Okamoto et al. · 2003 [cited by applicant]
US 20040137580A1 · Holgersson et al. · 2004 [cited by applicant]
US 20050069552A1 · Bleck et al. · 2005 [cited by applicant]
US 20050260222A1 · Gupta et al. · 2005 [cited by applicant]
US 20050265995A1 · Tomlinson et al. · 2005 [cited by applicant]
US 20060110429A1 · Reiff et al. · 2006 [cited by applicant]
US 20070105767A1 · Kharbanda et al. · 2007 [cited by applicant]
US 20080045493A1 · Drescher et al. · 2008 [cited by applicant]
US 20080286211A1 · Barker et al. · 2008 [cited by applicant]
US 20090054489A1 · Hauske · 2009 [cited by applicant]
US 20100016547A1 · Ito et al. · 2010 [cited by applicant]
US 20100227394A1 · Bleck et al. · 2010 [cited by applicant]
US 20100285014A1 · Cox et al. · 2010 [cited by applicant]
US 20130217864A1 · Cho et al. · 2013 [cited by applicant]
US 20130295084A1 · Hunter et al. · 2013 [cited by applicant]
US 20130316404A1 · Roers et al. · 2013 [cited by applicant]
US 20130336925A1 · Alvarez et al. · 2013 [cited by applicant]
US 20140024650A1 · Fukumoto et al. · 2014 [cited by applicant]
US 20140056895A1 · Baurin et al. · 2014 [cited by applicant]
US 20140072581A1 · Dixit et al. · 2014 [cited by applicant]
US 20140234962A1 · Alvarez et al. · 2014 [cited by applicant]
US 20150071948A1 · Lazar et al. · 2015 [cited by applicant]
US 20160068583A1 · McCauley et al. · 2016 [cited by applicant]
US 20160175458A1 · Alvarez et al. · 2016 [cited by applicant]
US 20170114098A1 · Aivado et al. · 2017 [cited by applicant]
US 20170226137A1 · Fujimoto et al. · 2017 [cited by applicant]
US 20170233447A1 · Qin · 2017 [cited by applicant]
US 20180179151A1 · Nagase et al. · 2018 [cited by applicant]
US 20180289825A1 · Alvarez et al. · 2018 [cited by applicant]
US 20190031611A1 · Fujimoto et al. · 2019 [cited by applicant]
US 20190040010A1 · Kajita et al. · 2019 [cited by applicant]
US 20190167590A1 · Zamloot et al. · 2019 [cited by applicant]
US 20200017444A1 · Kajita et al. · 2020 [cited by applicant]
US 20200115399A1 · Fujimoto et al. · 2020 [cited by applicant]
US 20200207715A1 · Kajita et al. · 2020 [cited by applicant]
US 20200207734A1 · Kajita et al. · 2020 [cited by applicant]
US 20200247747A1 · Hattori et al. · 2020 [cited by applicant]
US 20200255403A1 · Bogen et al. · 2020 [cited by applicant]
US 20200385345A1 · Daini et al. · 2020 [cited by applicant]
US 20200385346A1 · Fujimoto et al. · 2020 [cited by applicant]
US 20200392149A1 · Mikami et al. · 2020 [cited by applicant]
US 20210078955A1 · Nagase et al. · 2021 [cited by applicant]
US 20210155636A1 · Pennington et al. · 2021 [cited by applicant]
US 20210198240A1 · Oda et al. · 2021 [cited by applicant]
US 20210269420A1 · Fujimoto et al. · 2021 [cited by applicant]
US 20220017514A1 · Kajita et al. · 2022 [cited by applicant]
US 20220017517A1 · Yoshida et al. · 2022 [cited by applicant]
US 20220081441A1 · Ideue et al. · 2022 [cited by applicant]
US 20220194926A1 · Pennington et al. · 2022 [cited by applicant]
US 20230037557A1 · Ito et al. · 2023 [cited by applicant]
US 20230042358A1 · Miyanohana et al. · 2023 [cited by applicant]
US 20230192692A1 · Li et al. · 2023 [cited by applicant]
CN 101962413A · 2011 [cited by applicant]
CN 107787322A · 2018 [cited by applicant]
CN 108699065A · 2018 [cited by applicant]
EP 2836485B1 · 2018 [cited by applicant]
EP 3191468B1 · 2018 [cited by applicant]
EP 3663281A1 · 2020 [cited by applicant]
EP 3816154A1 · 2021 [cited by applicant]
EP 3895707A1 · 2021 [cited by applicant]
EP 3896060A1 · 2021 [cited by applicant]
JP 2003508023A · 2003 [cited by applicant]
JP 2003513656A · 2003 [cited by applicant]
JP 2003514552A · 2003 [cited by applicant]
JP 2004528014A · 2004 [cited by applicant]
JP 2006517191A · 2006 [cited by applicant]
JP 2008521489A · 2008 [cited by applicant]
JP 2010536341A · 2010 [cited by applicant]
JP 2022064180A · 2022 [cited by applicant]
WO 1999046392A1 · 1999 [cited by applicant]
WO 0103737A1 · 2001 [cited by applicant]
WO 0158950A1 · 2001 [cited by applicant]
WO 2002062375A1 · 2002 [cited by applicant]
WO 2004033651A2 · 2004 [cited by applicant]
WO 2004044006A1 · 2004 [cited by applicant]
WO 2004101740A2 · 2004 [cited by applicant]
WO 2005034863A2 · 2005 [cited by applicant]
WO 2007020889A1 · 2007 [cited by applicant]
WO 2007062844A1 · 2007 [cited by applicant]
WO 2007063907A1 · 2007 [cited by applicant]
WO 2008140595A2 · 2008 [cited by applicant]
WO 2009153960A1 · 2009 [cited by applicant]
WO 2010018233A1 · 2010 [cited by applicant]
WO 2010127029A1 · 2010 [cited by applicant]
WO 2010150192A1 · 2010 [cited by applicant]
WO 2011076781A1 · 2011 [cited by applicant]
WO 2011090762A1 · 2011 [cited by applicant]
WO 2011122923A2 · 2011 [cited by applicant]
WO 2012137982A2 · 2012 [cited by applicant]
WO 2012146628A1 · 2012 [cited by applicant]
WO 2012178137A1 · 2012 [cited by applicant]
WO 2013026833A1 · 2013 [cited by applicant]
WO 2013139697A1 · 2013 [cited by applicant]
WO 2013184942A1 · 2013 [cited by applicant]
WO 2014018572A2 · 2014 [cited by applicant]
WO 2014023673A1 · 2014 [cited by applicant]
WO 2014151910A1 · 2014 [cited by applicant]
WO 2014198880A1 · 2014 [cited by applicant]
WO 2015017548A2 · 2015 [cited by applicant]
WO 2015117930A1 · 2015 [cited by applicant]
WO 2016082677A1 · 2016 [cited by applicant]
WO 2016100788A1 · 2016 [cited by applicant]
WO 2016101119A1 · 2016 [cited by applicant]
WO 2016133160A1 · 2016 [cited by applicant]
WO 2017035354A1 · 2017 [cited by applicant]
WO WO2017135306A1 · 2017 [cited by examiner]
WO 2017165464A1 · 2017 [cited by applicant]
WO 2018005226A2 · 2018 [cited by applicant]
WO 2019027058A1 · 2019 [cited by applicant]
WO 2019063605A1 · 2019 [cited by applicant]
WO 2019191327A1 · 2019 [cited by applicant]
WO 2020004536A1 · 2020 [cited by applicant]
WO 2020004537A1 · 2020 [cited by applicant]
WO 2020122092A1 · 2020 [cited by applicant]
WO 2020122093A1 · 2020 [cited by applicant]
WO 2020158958A1 · 2020 [cited by applicant]
WO 2020167701A1 · 2020 [cited by applicant]
WO 2020167706A1 · 2020 [cited by applicant]
WO 2021026047A1 · 2021 [cited by applicant]
WO 2021048821A1 · 2021 [cited by applicant]
WO 2021106975A1 · 2021 [cited by applicant]
WO 2021108628A1 · 2021 [cited by applicant]
WO 2021142083A1 · 2021 [cited by applicant]
WO 2022014680A1 · 2022 [cited by applicant]
WO 2022040058A1 · 2022 [cited by applicant]
WO 2022040070A1 · 2022 [cited by applicant]
WO 2022051583A1 · 2022 [cited by applicant]
WO 2022051596A1 · 2022 [cited by applicant]
WO 2022094012A1 · 2022 [cited by applicant]
WO 2022109117A1 · 2022 [cited by applicant]
WO 2022119888A1 · 2022 [cited by applicant]
WO 2022132696A1 · 2022 [cited by applicant]
WO 2022140316A1 · 2022 [cited by applicant]
WO 2022140317A1 · 2022 [cited by applicant]
WO 2022187231A1 · 2022 [cited by applicant]
WO 2022207935A1 · 2022 [cited by applicant]
WO 2022233872A1 · 2022 [cited by applicant]
WO 2022250108A1 · 2022 [cited by applicant]
WO 2022269049A1 · 2022 [cited by applicant]
WO 2023017180A1 · 2023 [cited by applicant]
Cox, C. D., et al., “Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding”, Bioorganic & Medicinal Chemistry Letters, 19(11), DOI:10. 1016/J.BMCL.2… [cited by applicant]
Irukayama-Tomobe, Y. , et al., “Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models”, PNAS, vol. 114, No. 22, 5731-5736. [cited by applicant]
McGaughey, G. , et al., “Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs”, J. Comput. Aided Mol. Des., 28, 5-12. [cited by applicant]
Nagahara, T. , et al., “Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists”, J. Med. Chem., 58, 7931-7937. [cited by applicant]
Sabnis, R. W., “Novel 5-Alkyl Pyrrolidine Orexin Receptor Agonists for Treating Sleep Disorders”, ACS Med. Chem. Lett., vol. 11, 11 (online at https://dx.doi.org/10.1021/acsmedchemlett.0c00501), Sep. 29, 2020, 2085-2086. [cited by applicant]
Turku, A. , et al., “Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity”, PLOS ONE, 12(6): e0178526 (online at doi:10.1371/journal.pone.0… [cited by applicant]
Yukitake, H. , et al., “TAK-925, an orexin 2 receptor-selective agonist, shows robust wakepromoting effects in mice”, Pharmacology, Biochemistry and Behavior, 187, 172794. [cited by applicant]
Publications Related to P18510-IL1RA Human, www.uniprot.org. [cited by applicant]
Uniprot Protein Database, Protein Accession Q8N3074, Human Mucin 20, accessed on Oct. 16, 2016. [cited by applicant]
“3-(Cycohexylmethoxy)piperidine”, PubChem, CID 43196817, create date Jul. 21, 2009. [cited by applicant]
“4-[Pyrrolidin-3-yloxy)methyl]piperidine”, Pubchem CID 130141993, Create date: Oct. 7, 2017. [cited by applicant]
Arai, R., et al., “Design of the linkers which effectively separate domains of a bifunctional fusion protein”, Protein Eng, 14(8), 529-532, 2001. [cited by applicant]
Cao, W., et al., “Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobuln V and mucin domains and occurs via the mitogen-activated protein kinase pathway”, Immunology, … [cited by applicant]
Chen, X., et al., “Fusion Protein Linkers: Property, Design and Functionality”, Advanced Drug Delivery Reviews, 65, 1357-1369, 2012. [cited by applicant]
Czajkowsky, D. M., et al., “Fc-fusion proteins: new developments and future perspectives”, EMBO Mol Med, 4(10)DOI 10.1002/emmm.201201379, Jul. 26, 2012, 1015-1028. [cited by applicant]
Ding, Y., et al., “A Single Amino Acid Determines the Immunostimulatory Activity of Interleukin 10”, J. Exp. Med., 191(2), 213-223, 2000. [cited by applicant]
Fontenot, D., et al., “Human Immunodeficiency Virus (HIV) antigens: Structure and Serology of Multivalent Human Mucin MUC1-HIV V3 Chimeric Proteins”, PNAS, 92, 315-319, 1995. [cited by applicant]
Hasanain, S., “Effect of Topical IL-1 RA On Signs And Symptoms Of Dry Eye Disease In Patients With Ocular Graftversus—host Disease (GVHD)”, ARVO Annual Meeting, 53, Abstract 579, 2012. [cited by applicant]
Linderholm, A. L, et al., “Immunoglobulin Fc-Fusion Proteins Part 2: Therapeutic Uses and Clinical Development”, Bioprocess Intl, 12(10), Nov. 1, 2014, 1-7, 2014. [cited by applicant]
Nomellini, J. F, et al., “S-Layer-Mediated Display of the Immunoglobulin G-Binding Domain of Streptococcal Protein G on the Surface of Caulobacter crescenius: Development of an Immunoactive Reagent”, Appl. Environ. Micr… [cited by applicant]
Shen, H., et al., “Deletion of the Linker Connecting the Catalytic and Cellulose-Binding Domains of Endoglucanase A (CenA) of Cellulomonas fimi Alters Its Conformation and Catalytic Activity”, The Journal of Biological … [cited by applicant]
Shimamoto, G., et al., “Peptibodies: A flexible alternative format to antibodies”, MABS, 4(5), 586-591, 2012. [cited by applicant]
Vallee, S., et al., “Pulmonary Administration of Interferon Beta-1a-Fc Fusion Protein in Non-Human Primates Using an Immunoglobulin Transport Pathway”, J linterferon & Cytokine Res, 32(4), 178-184, 2012. [cited by applicant]
Wriggers, W., et al., “Control of Protein Functional Dynamics by Peptide Linkers”, Biopolymers (Peptide Science), 80, 736-746, 2005. [cited by applicant]
Wu, B., et al., “Pharmacokinetics of Peptide-Fe Fusion Proteins”, J Pharm Sci., 103(1), 53-64, 2014. [cited by applicant]
Yoon, S., et al., “Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex”, J Biol Chem., 281(46), 35088-96, 2006. [cited by applicant]
Zhang, J., et al., “Design and optimization of a linker for fusion protein construction”, Progress in Natural Science, 19, 1197-1200, 2009. [cited by applicant]
Zhao, L., et al., “Eradication of non-Hodgkin lymphoma through the induction of tumor-specific T-cell immunity by CD20-Flex BiFP”, Blood, 122(26), 4230-6, 2013. [cited by applicant]
Zheng, X. X, et al., “Administration of noncytolytic IL-10/Fc in murine models of lipopolysaccharide-induced septic shock and allogeneic islet transplantation”, J. Immunol., 154(10), May 15, 1995, 5590-5600. [cited by applicant]
Zheng, X. X, et al., “I L-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice”, J. Immunol., 163(7), Oct. 1, 1999, 4041-4048. [cited by applicant]
Zheng, X. X, et al., “Noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice”, J. Immunol., 158(9), May 1, 1997, 4507-4513. [cited by applicant]