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Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders

A modulator, G protein technology, applied in the direction of cardiovascular system diseases, animal/human protein, hormone receptor, etc., can solve the problem of mortality reduction and other issues

Inactive Publication Date: 2006-07-19
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, despite advances in CHF medicine over the past 10 years (ACE inhibitors, beta blockers), only a 20% to 30% reduction in mortality has been shown with current optimal therapy
In the future, development of better drugs and identification of new therapeutic targets will likely improve clinical outcomes in CHF patients

Method used

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  • Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders
  • Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders
  • Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders

Examples

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preparation example Construction

[0778] Incorporate activity levels into target molecules 125 The synthetic method of I comprises:

[0779] A. Sandmeyer and similar reactions - This procedure converts an aryl or heteroaryl amine to a diazonium salt (such as tetrafluoroborate) and subsequently reacts with Na 125 I convert it into 125 I labeled compound. A representative procedure is reported by Zhu, D.-G. and colleagues in J. Org. Client. 2002, 67, 943-948.

[0780] B. The ortho position of phenol 125 Iodination - This procedure involves the incorporation of 125 I, as reported by Collier, T.L. and colleagues in J. Labeled Compd Radiopharm. 1999, 42, S264-S266.

[0781] C. Aryl and heteroaryl bromides with 125 Exchange of I—This method is usually a one-two step method. The first step is in trialkyltin halides or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ] in the presence of (for example) Pd catalyzed reactions [ie Pd(Ph 3 P) 4 ] or conversion of an aryl or heteroaryl bromide to the correspondin...

example

[0786] The following examples are provided only to illustrate and not to limit the invention. Although specific nucleic acid and amino acid sequences are disclosed herein, it is believed that one skilled in the art will be able to modify these sequences slightly while obtaining results identical or substantially similar to those reported below.

[0787] The following examples are offered by way of illustration only and not by way of limitation. Those skilled in the art will be able to devise equivalent analyzes and methods based on the disclosure herein, all of which form a part of the present invention.

[0788] Those skilled in the art can use various expression vectors to achieve the purpose of producing a polypeptide of interest in a cell. A suitable vector is pCMV, which is used in certain embodiments. This vector was deposited with the American Type Culture Collection on October 13, 1998 under the terms of the Budapest Treaty for the International Recognition of the De...

example 1

[0791] Full-length clone of human endogenous RUP40

[0792] The polynucleotide encoding human endogenous RUP40 was cloned from Clontech Multiple Tissue cDNA Panel, Cat. No. K1425-1 (especially the complementary sequence of the first-strand cDNA of human fetal spleen).

[0793] The clones were generated by polymerase chain reaction using Advantage HF-2 polymerase (Clontech cat# K1914-y) and using the following gene specific primers:

[0794] 5′-ATAT GGTACC ATGAAATCCCCAAGGAGAACCACTTTGTGCC-3' (SEQ ID NO: 7; antisense)

[0795] 5′-ATAT GCGGCCGC TTAGTTGAGCAACGAAGAAGCACTGGATGAG-3' (SEQ ID NO: 8; sense).

[0796] Antisense primers contain a KpnI restriction site underlined, and a start codon in bold / italics. The sense primer contains a NotI restriction site underlined, and a stop codon in bold / italics.

[0797] Amplification was performed using Advantage HF-2 polymerase in a 50 μl reaction by the following cycle in which steps 2 to 3 were repeated 35 times: Step 1: 94.0°C, 15 ...

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Abstract

The present invention relates to methods of identifying whether a candidate compound is a modulator of a G protein-coupled receptor (GPCR). In some embodiments, the GPCR is mammalian, preferably human. In some embodiments, the GPCR is expressed endogenously by cardiomyocytes. In some embodiments, the GPCR is coupled to Gq. In some embodiments, the GPCR increases the intracellular level of inositol 1,4,5-triphosphate (IP3). In some embodiments, a modulator of the GPCR is a modulator of cardiomyocyte hypertrophy. The present invention further relates to methods of using a modulator of the GPCR. Preferred modulators are inverse agonists and antagonists. Inverse agonists and antagonists of the invention are useful as therapeutic agents for the prevention or treatment of heart disease, including hypertrophic cardiomyopathy and congestive heart failure, in particular hypertrophic cardiomyopathy resulting from post-myocardial infarction remodeling, cardiac valve disease, sustained cardiac afterload, myocarditis, and familial hypertrophic cardiomyopathy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority over the following Provisional Application, US Patent Provisional Application No. 60 / 480,046, filed June 20, 2003, filed with the USPTO by US Express Mail on the date indicated. The entire disclosure of the above application is incorporated herein by reference. technical field [0003] The present invention relates to methods of identifying whether a candidate compound is a G protein coupled receptor (GPCR) modulator. In some embodiments, the GPCR is a mammalian GPCR, preferably a human GPCR. In some embodiments, the GPCR is endogenously expressed by cardiomyocytes. In some embodiments, the GPCR can be coupled to Gq. In some embodiments, the GPCR increases intracellular inositol 1,4,5-triphosphate (IP3) content. In some embodiments, a GPCR modulator is a cardiomyocyte hypertrophy modulator. The invention further relates to methods of using a GPCR modulator. Preferred modulators are i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/566G01N33/68A01K67/027C07K14/72G01N33/74
CPCC07K2319/00A01K2227/105G01N33/6893A01K2267/03C12N2799/022G01N2333/726A01K67/027C07K14/705A01K2217/075G01N2800/32C07K14/723G01N33/74A01K67/0276A01K2217/072G01N33/76A01K67/0275G01N2800/325A61P43/00A61P9/00A61P9/04A61P9/10
Inventor 约翰·W·亚当斯丹尼尔·康诺利
Owner ARENA PHARMA
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