IP Library › Granted Patent US 9,133,261
Granted Patent B2
US 9,133,261 · App. 14/157,770 · Granted Sep 15, 2015

Ghrelin analogs

Inventors: Zheng Xin Dong (Holliston, MA); Yeelana Shen (Franklin, MA)
Assignee: Ipsen Pharma S.A.S.
C07K14/61A61K38/22C07K14/575C07K14/60A61K38/00
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Quick Facts
Patent No.
US 9,133,261
App. No.
14/157,770
Granted
Sep 15, 2015
Kind
B2
Abstract

The invention comprises peptidyl analogs that possess agonist or antagonist ghrelin activity, along with therapeutic and non-therapeutic uses thereof.

Claims (125)

1. A compound selected from the group consisting of:

(Aib 2 , Glu 3 (NH-Hexyl), A6c 5 )hGhrelin(1-28)-NH 2 (SEQ ID NO:223);

(Aib 2,6 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:225);

(Aib 2 , Glu 3 (NH-Hexyl), Act 6 )hGhrelin(1-28)-NH 2 (SEQ ID NO:226);

(Aib 2 , Glu 3 (NH-Hexyl), 3Pal 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:227);

(Aib 2 , Glu 3 (NH-Hexyl), Dmt 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:228);

(Aib 2 , Glu 3 (NH-Hexyl), Thz 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:229);

(Aib 2 , Glu 3 (NH-Hexyl), A5c 5 )hGhrelin(1-28)-NH 2 (SEQ ID NO:230);

(Aib 2,5 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:231);

(Aib 2 , Glu 3 (NH-Hexyl), hLeu 5 )hGhrelin(1-28)-NH 2 (SEQ ID NO:232);

(Aib 2 , Glu 3 (NH-Hexyl), Thr 6 )hGhrelin(1-28)-NH 2 (SEQ ID NO:233);

(Aib 2 , Glu 3 (NH-Hexyl), Abu 6 )hGhrelin(1-28)-NH 2 (SEQ ID NO:234);

(Aib 2 , Glu 3 (NH-Hexyl), 4Hyp 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:235);

(Aib 2 , Glu 3 (NH-Hexyl), Pip 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:236);

(Aib 2 , Glu 3 (NH-Hexyl), Dhp 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:237);

(Aib 2 , Glu 3 (NH-Hexyl), Ktp 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:238);

(Aib 2,8 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:239);

(Aib 2 , Glu 3 (NH-Hexyl), 2Pal 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:240);

(Aib 2 , Glu 3 (NH-Hexyl), 4Pal 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:241);

(Aib 2 , Glu 3 (NH-Hexyl), Taz 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:242);

(Aib 2 , Glu 3 (NH-Hexyl), 2Thi 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:243);

(Aib 2 , Glu 3 (NH-Hexyl), 2Fua 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:244);

(Aib 2 , Glu 3 (NH-Hexyl), Apc 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:245);

(Aib 2,9 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:246);

(Aib 2,10 , Glu3(NH-Hexyl))hGhrelin(1-28)-NH2 (SEQ ID NO:247);

(Aib 2 , Glu 3 (NH-Hexyl), A6c 5 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:272);

(Aib 2,6 , Glu 3 (NH-Hexyl), A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:274);

(Aib 2 , Glu 3 (NH-Hexyl), Act 10 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:275);

(Aib 2 , Glu 3 (NH-Hexyl), 3Pal 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:276);

(Aib 2 , Glu 3 (NH-Hexyl), Dmt 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:277);

(Aib 2 , Glu 3 (NH-Hexyl), Thz 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:278);

(Aib 2 , Glu 3 (NH-Hexyl), A5c 5 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:279);

(Aib 2,5 , Glu 3 (NH-Hexyl), A5c 12 ,Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:280);

(Aib 2 , Glu 3 (NH-Hexyl), Cha 5 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:281);

(Aib 2 , Glu 3 (NH-Hexyl), Thr 6 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:282);

(Aib 2 , Glu 3 (NH-Hexyl), Abu 6 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:283);

(Aib 2 , Glu 3 (NH-Hexyl), 4Hyp 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:284);

(Aib 2 , Glu 3 (NH-Hexyl), Pip 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:285);

(Aib 2 , Glu 3 (NH-Hexyl), Dhp 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:286);

(Aib 2 , Glu 3 (NH-Hexyl), Ktp 7 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:287);

(Aib 2,8 , Glu 3 (NH-Hexyl), A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:288);

(Aib 2 , Glu 3 (NH-Hexyl), 2Pal 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:289);

(Aib 2 , Glu 3 (NH-Hexyl), 4Pal 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:290);

(Aib 2 , Glu 3 (NH-Hexyl), Taz 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:291);

(Aib 2 , Glu 3 (NH-Hexyl), 2Thi 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:292);

(Aib 2 , Glu 3 (NH-Hexyl), 2Fua 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:293);

(Aib 2 , Glu 3 (NH-Hexyl), Apc 9 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:294);

(Aib 2,9 , Glu 3 (NH-Hexyl), A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:295);

(Aib 2,12 , Glu 3 (NH-Hexyl), 4Pal 9 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:296);

(Aib 2,10 , Glu 3 (NH-Hexyl), A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:297);

(Aib 2 , Glu 3 (NH-Hexyl), A6c 5 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:298);

(Aib 2,6 , Glu 3 (NH-Hexyl), A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:300);

(Aib 2 , Glu 3 (NH-Hexyl), Act 6 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:301);

(Aib 2 , Glu 3 (NH-Hexyl), 3Pal 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:302);

(Aib 2 , Glu 3 (NH-Hexyl), DMt 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:303);

(Aib 2 , Glu 3 (NH-Hexyl), Thz 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:304);

(Aib 2 , Glu 3 (NH-Hexyl), A5c 5 , 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:305);

(Aib 2,5 , Glu 3 (NH-Hexyl), A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:306);

(Aib 2 , Glu 3 (NH-Hexyl), hLeu 5 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:307);

(Aib 2 , Glu 3 (NH-Hexyl), Cha 5 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:308);

(Aib 2 , Glu 3 (NH-Hexyl), Thr 6 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:309);

(Aib 2 , Glu 3 (NH-Hexyl), Abu 6 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:310);

(Aib 2 , Glu 3 (NH-Hexyl), 4Hyp 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:311);

(Aib 2 , Glu 3 (NH-Hexyl), Pip 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:312);

(Aib 2 , Glu 3 (NH-Hexyl), Dhp 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:313);

(Aib 2 , Glu 3 (NH-Hexyl), Ktp 7 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:314);

(Aib 2,8 , Glu 3 (NH-Hexyl), A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:315);

(Aib 2 , Glu 3 (NH-Hexyl), 2Pal 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:316);

(Aib 2 , Glu 3 (NH-Hexyl), 4Pal 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:317);

(Aib 2 , Glu 3 (NH-Hexyl), Taz 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:318);

(Aib 2 , Glu 3 (NH-Hexyl), 2Thi 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:319);

(Aib 2 , Glu 3 (NH-Hexyl), 2Fua 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:320);

(Aib 2 , Glu 3 (NH-Hexyl), Apc 9 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:321);

(Aib 2,9 , Glu 3 (NH-Hexyl), A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:322);

(Aib 2,10 , Glu 3 (NH-Hexyl), A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 (SEQ ID NO:323); and

(Aib 2 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:329);

or a pharmaceutically acceptable salt thereof,

wherein:

Abu is α-aminobutyric acid,

A5c is 1-amino-1-cyclopentanecarboxylic acid,

A6c is 1-amino-1-cyclohexanecarboxylic acid,

Act is

Aib is α-aminoisobutyric acid,

Apc is

Cha is β-cyclohexylalanine,

Dhp is 3,4-dehydroproline,

Dmt is 5,5-dimethylthiazolidine-4-carboxylic acid,

2Fua is β-(2-furyl)-alanine,

Ktp is 4-ketoproline,

Orn is ornithine,

2Pal is β-(2-pyridinyl)alanine,

3Pal is β-(3-pyridinyl)alanine,

Pip is pipecolic acid,

Taz is

2Thi is β-(2-thienyl)alanine,

Thz is thiazolidine-4-carboxylic acid, and

Glu(NH-Hexyl) is

2. The compound of claim 1 , selected from:

(Aib 2 , Glu 3 (NH-Hexyl), Taz 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:242);

(Aib 2 , Glu 3 (NH-Hexyl), Thr 6 )hGhrelin(1-28)-NH 2 (SEQ ID NO:233);

(Aib 2 , Glu 3 (NH-Hexyl), 2Thi 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:243);

(Aib 2 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:329);

(Aib 2 , Glu 3 (NH-Hexyl), 4Hyp 7 )hGhrelin(1-28)-NH 2 (SEQ ID NO:235);

(Aib 2,8 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:239);

(Aib 2,12 , Glu 3 (NH-Hexyl), 4Pal 9 , Orn 15 )hGhrelin(1-28)-NH 2 (SEQ ID NO:296);

(Aib 2 , Glu 3 (NH-Hexyl), 4Pal 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:241);

(Aib 2 , Glu 3 (NH-Hexyl), 3Pal 9 )hGhrelin(1-28)-NH 2 (SEQ ID NO:227);

(Aib 2,10 , Glu 3 (NH-Hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:247);

or a pharmaceutically acceptable salt thereof,

wherein:

Aib is α-aminoisobutyric acid,

Apc is

4Hyp is (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid,

Orn is ornithine,

3Pal is β-(3-pyridinyl)alanine,

4Pal is β-(4-pyridinyl)alanine,

Taz is

2Thi is B-(2-thienylalanine, and

Glu(NH-Hexyl) is

3. The compound of claim 2 , wherein said compound is

(Aib 2 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2 (SEQ ID NO:329)

or a pharmaceutically acceptable salt thereof,

wherein:

Aib is α-aminoisobutyric acid, and

Glu(NH-Hexyl) is

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2014
From: DONG, ZHENG XIN; SHEN, YEELANA
To: BIOMEASURE, INCORPORATED
Reel/Frame 032040/0416 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2014
From: BIOMEASURE, INCORPORATED
To: IPSEN PHARMA S.A.S.
Reel/Frame 032040/0468 →
Continuity (5)
Continuation 12456429 · Jun 16, 2009
Continuation 10522398
Provisional Application 60397834 · Jul 23, 2002
Provisional Application 60427488 · Nov 19, 2002
Related Publication 20140135260A1 · May 15, 2014