Selective PYY compounds and uses thereof

一种化合物、选自的技术，应用在消化系统、药物组合、动物/人类肽等方向，能够解决血压升高等问题

Active Publication Date: 2018-03-27
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, activation of Y1 and Y5 receptors can lead to increased blood pressure

Method used

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  • Selective PYY compounds and uses thereof
  • Selective PYY compounds and uses thereof
  • Selective PYY compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0776] Embodiment 1: the synthesis of PYY compound

[0777] The PYY compounds of the present invention are synthesized according to the general preparation methods described above.

[0778] hPYY(3-36)

[0779] IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-NH 2

[0780] Calculated MW: 4049.6 g / mol

[0781] MALDI MS, measured: 4048.2g / mol

[0782] Compound 1

[0783] N{ε-7}-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)-butyryl]amino]butyryl]-[ Arg4, Lys7, Gln18, Tyr28, Trp30, Leu31] hPYY(3-36)

[0784]

[0785] Calculated MW (average): 4840.37 g / mol

[0786] 457_LCMS01: Measured [M+5H] 5+969.06

[0787] The amino acid sequence of [Arg4, Lys7, Gln18, Tyr28, Trp30, Leu31] hPYY(3-36) is given in SEQ ID NO:3.

[0788] Compound 2

[0789] N{α-4}-(3-methylbutyryl)-N{ε-7}-[(4S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyryl]-[Arg4 , Lys7, Gln18, Tyr28, Trp30, Leu31] hPYY(4-36)

[0790]

[0791] Calculated MW (average): 4682.21 g / mol

[0792] 457_...

Embodiment 2

[1218] Example 2: Receptor potency of PYY compounds

[1219] The purpose of this example is to test the activity or potency of PYY compounds in vitro. Y2 in vitro potency is a measure of activation of the human Y2 receptor subtype in a whole cell assay.

[1220] The Y2 potency of the PYY compound of Example 1 was determined using the Actone functional potency assay described below. hPYY(3-36) (SEQ ID NO: 2) is included by reference.

[1221] Actone Functional Potency Test

[1222] Neuropeptide Y (NPY) receptors are G i - A coupled seven-transmembrane receptor that signals via a cAMP-dependent pathway primarily by inhibiting adenylyl cyclase activity, resulting in a decrease in cAMP production from ATP. The Actone assay is based on a modified calcium channel with selective binding to cAMP, resulting in cellular calcium influx, which is detected by a calcium-responsive dye. To measure reduced cAMP levels resulting from NPY receptor activation, the β1 / β2-adrenoceptor agoni...

Embodiment 3

[1228] Example 3: Y1, Y2, Y4 and Y5 Receptor Subtype Binding

[1229] The purpose of this example is to test the in vitro binding of PYY compounds to Y1, Y2, Y4 and Y5 receptor subtypes, respectively. Receptor binding affinity is a measure of the affinity of a compound for the human Y1, Y2, Y4 and Y5 receptor subtypes, respectively.

[1230] In vitro binding of the PYY compound of Example 1 was determined in a scintillation proximity assay (SPA) as described below. hPYY(3-36) (Example X, SEQ ID NO: 2) is included by reference.

[1231] Scintillation Approach Analysis (SPA)

[1232] Cell lines expressing NPY receptors. All cells were stored at +37°C with 5% CO 2 cultured in a humidified atmosphere. BHK-21 clone 6-482-8 cells (P25929, NPY1R_HUMAN, Uniprot), which can inducibly express human Y1 receptors, were treated with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin (P / S), 1 mg / ml G418 antibiotic, 1 mg / ml hygromycin B antibiotic and 1% non-...

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PUM

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Abstract

The invention relates to PYY compounds with the amino acid modifications 7Lys, 30Trp, and 31Leu, and in addition to these, 22Ile and / or 28Tyr, and derivatives thereof. The compounds of the invention are selective Y2 receptor agonists. The invention also relates to pharmaceutical compositions comprising such PYY compounds and pharmaceutically acceptable excipients, as well as the medical use of thePYY compounds.

Description

technical field [0001] The present invention relates to analogs and / or derivatives of peptide YY (PYY) and their pharmaceutical use. [0002] Incorporation by Reference of Sequence Listings [0003] The Sequence Listing titled "Sequence Listing" is 13999 bytes, created on June 10, 2015 and June 12, 2016 and incorporated herein by reference. Background technique [0004] PYY is released from L-cells in the distal small intestine and colon during a meal. PYY is known to have peripheral effects in the gastrointestinal (GI) tract and also functions primarily as a satiety signal. PYY is naturally secreted as a 36 amino acid peptide with a C-terminal amide (PYY(1-36)), but is cleaved to PYY(3-36), which constitutes approximately 50% of circulating PYY. The enzyme responsible for this degradation is dipeptidyl peptidase IV (DPPIV). PYY(3-36) is rapidly eliminated by proteases and other clearance mechanisms. PYY(3-36) has been reported to have a half-life of <30 minutes in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575A61K38/22A61K47/64A61P3/04
CPCC07K14/575A61K47/542A61K38/00A61P1/00A61P13/10A61P19/02A61P25/00A61P3/04A61P9/00A61P3/10C07K14/47
Inventor S.奥斯特加亚尔德C.詹斯森B.S.沃夫A.桑夫里德森
Owner NOVO NORDISK AS
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