Pyrazole derivatives which modulate human 5-serotonin receptors

A compound and composition technology, applied in the field of small molecule regulators

Inactive Publication Date: 2003-04-16
ARENA PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both have antipsychotic effects, but typical treatment also includes concomitant motor-related side

Method used

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  • Pyrazole derivatives which modulate human 5-serotonin receptors
  • Pyrazole derivatives which modulate human 5-serotonin receptors
  • Pyrazole derivatives which modulate human 5-serotonin receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Non-endogenous, constitutively activated human 5-HT receptor 5-HT 2C and 5-HT 2A production

[0057] A. Constitutively active 5-HT 2C Construction of receptor cDNA

[0058] 1. Endogenous human 5-HT 2C

[0059] Encodes endogenous human 5-HT 2C The cDNA of the receptor was obtained from human brain polyadenylic acid (poly-A + ) obtained from RNA. 5' and 3' primers were derived from the 5' and 3' untranslated regions and contained the following sequences:

[0060] 5'-GACCTCGAGGTTGCTTAAGACTGAAGCA-3' (SEQ.ID.NO.: 1),

[0061] 5'-ATTTCTAGACATATGTAGCTTGTACCGT-3' (SEQ. ID. NO.: 2).

[0062] Using TaqPlus TM Precision polymerase (Stratagene) or rTth TM Polymerase (PerkinElmer) and the buffer system provided by the manufacturer were used for PCR, each primer was 0.25 μM, and each of the four nucleotides was 0.2 mM. The cycle conditions were 94°C for 1 minute, 57°C for 1 minute, and 72°C for 2 minutes, and the cycle was 30 times. The 1.5 kb PCR fragment was digested w...

Embodiment 2

[0114] receptor expression

[0115] A.pCMV

[0116] Although a variety of expression vectors are available to those skilled in the art, the most preferred vector for use with the endogenous and non-endogenous receptors discussed in the present invention is pCMV. This vector was deposited with the American Type Culture Collection (ATCC) on October 13, 1998 (10801 University Blvd., Manassas, VA 20110-2209 USA) in accordance with the provisions of the Budapest Treaty on the International Recognition of Deposits of Microorganisms for the Purposes of Patent Procedure. The DNA was tested by the ATCC and certified viable. The ATCC has assigned the following accession number to pCMV: ATCC #203351. See Figure 8.

[0117] B. Transfection Procedure

Embodiment 3

[0120] Protocol: GTP Membrane-Bound Scintillation Proximity Assay

[0121] application[ 35 The advantages of constitutive activation of the GTPγS binding assay are: (a) [ 35 S] GTPγS binding is universal to all G protein-coupled receptors; (b)[ 35 S]GTPγS binds near the surface of the cell membrane, where molecules affecting intracellular cascades are less likely to be encountered. Preferably a GPCR: fusion protein is used. This test utilizes G protein-coupled receptor stimulation [ 35 S] The ability of GTPγS to bind to cell membranes expressing relevant receptors. Therefore, this assay can be used to directly screen compounds at the disclosed 5-HT receptors.

[0122] A scintillation proximity experiment was used to monitor [ 35 S] GTPγS interacts with endogenous human 5-HT expressed in, for example, COS cells 2C Receptor cell membrane binding. Briefly, a preferred experimental procedure is to prepare the test substance in 20 mM HEPES, pH 7.4, containing 0.3 nM [ 35 S...

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Abstract

Disclosed herein are non-endogenous, constitutively activated forms of the human 5-HT2A and human 5-HT2C receptors and uses of such receptors to screen candidate compounds. Further disclosed herein are candidate compounds identified by the screening method which act at the 5HT2A receptors. Yet further disclosed is a new class of compounds (I) which act at the 5HT2A receptors. This new class encompasses the candidate compounds. In Formula (A) W is F, Cl, Br, I, C1-8 straight chain or branched alkyl, C3-8 cycloalkyl, C4-9 alkylcycloalkyl, or C2-8 alkenyl; X is O or S or NR<2>; Y is NR<3>R<4>, or (CH2)mR<5>, or O(CH2)nR<6>; m is an integer between 0 and 4, inclusive; n is an integer between 0 and 4, inclusive; Z is H, C1-8 straight chain or branched alkyl, C3-8 cycloalkyl, C4-9 alkylcycloalkyl, or C2-8 alkenyl; R<1>, R<2>, R<3> and R<10> are as defined in the application.

Description

[0001] U.S. Provisional Application 60 / 152,708, filed September 7, 1999, U.S. Provisional Application 60 / 112,909, filed December 18, 1998, U.S. Provisional Application 60 / 123,000, filed March 5, 1999, and all of Benefit of US Patents 09 / 292,071, 09 / 292,072, and 09 / 292,069, filed April 14, 1999. field of invention [0002] The present invention relates to small molecule regulators of non-endogenous, constitutively active serotonin receptors; preferably, the small molecule regulators are preferentially selected from human 5HT 2A human 5HT 2C receptor; and most preferably, the small molecule modulator is 5HT 2A Receptor inverse activator. Background of the invention [0003] I. G protein-coupled receptors [0004] G protein-coupled receptors all have the same structural motif (motif). All of these receptors have seven sequences of 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The transmembrane helices are connected betwee...

Claims

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Application Information

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IPC IPC(8): A61P25/00C07DC07D231/12C07D231/16C07D409/12C07K14/705
CPCC07D231/12C07K14/70571C07D409/12C07D231/16A61P25/00
Inventor 多米尼克·P·比汉奈杰尔·R·A·比利德里克·T·查默斯理查德·J·福斯特罗伯特·C·格伦迈克尔·S·劳利斯蓁·W·廖求恩·刘弗里德里克·门扎奇约瑟夫·F·鲁索朱利安·R·史密斯威廉·J·汤姆森
Owner ARENA PHARMA
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