CN111939160A - A selective adenosine A1Molecules with receptor antagonistic activity - Google Patents

A selective adenosine A1Molecules with receptor antagonistic activity Download PDF

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CN111939160A
CN111939160A CN201910547371.4A CN201910547371A CN111939160A CN 111939160 A CN111939160 A CN 111939160A CN 201910547371 A CN201910547371 A CN 201910547371A CN 111939160 A CN111939160 A CN 111939160A
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adenosine
receptor
dmso
compound
cpd
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林建平
李冬梅
魏宇
王目阔
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Nankai University
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Nankai University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention provides 1 selective adenosine A1A receptor antagonist. The present invention is based on the integration of the existing adenosine A1Receptor ligands and activity data, virtual screening and in vitro biological assay methods, first finding a receptor having A1/A2ASelective novel adenosine A1Receptor antagonist G856-1381(4H-Pyrimido [5, 4-b ]]indol‑4‑one，3，5‑dihydro‑3‑(2‑propen‑1‑yl)‑2‑[(2‑pyridinylmethyl)thio]-). The compound is mixed with adenosine A1IC of receptor binding assay50Is 1.54. mu.M, Ki0.70 μ M; with adenosine A2AReceptor-bound IC5047.83 μ M and a Ki of 38.5 μ M. Further functional experiments (A)1antaconist cAMP assay) shows that it is adenosine A1IC for antagonism of receptor50It was 1.260. mu.M.

Description

A selective adenosine A1Molecules with receptor antagonistic activity
Technical Field
The invention relates to the field of small molecule drugs, and more specifically relates to selective adenosine A1A receptor antagonist.
Background
Adenosine is a ubiquitous modulator of a variety of physiological activities, particularly in the cardiovascular and nervous systems, and modulates a variety of physiological functions through interaction with specific cell surface receptors. There are four known subtypes of adenosine receptors, A1、A2A、A2B、A3Belonging to the family of G protein-coupled receptors. Adenosine A1And A3The receptor down-regulates cellular cAMP levels by coupling with G proteins that inhibit adenylate cyclase, whereas adenosine A2AAnd A2BThe receptor upregulates intracellular cAMP levels by coupling to G proteins that activate adenylate cyclase. Through these receptors, adenosine regulates a wide range of physiological functions.
Adenosine A1Receptors are an attractive pharmacological target and are expressed throughout the brain, including the cortex, hippocampus, and striatum. The antagonist can be used as kidney protectant, cognitive enhancer, antiasthmatic agent and central nervous system medicine. Adenosine A1Receptor antagonists play a potential therapeutic role in inflammatory diseases, and have been shown to be effective in rodent models of asthma and inflammation. There are reports showing adenosine A1Antagonists can reduce infarct size and have therapeutic potential in diseases such as hypertension and congestive heart failure. In addition, adenosine A1The receptor is involved in regulating intestinal motility, adenosine A1Activation of the receptor results in inhibition of the propulsive motor activity of ileus, and antagonists are capable of blocking A1The receptor can restore normal motor function of intestinal tract, and does not cause diarrhea, adenosine A1Receptor antagonists are potential treatments for various colonic functional-motility syndromes, including constipation and post-operative ileusAnd (4) strategy.
Thus selective adenosine A1Discovery of receptor antagonists for adenosine A1The treatment of related diseases caused by high expression or high activity of the receptor is of great significance.
Disclosure of Invention
The inventor establishes a random forest (random forest) classification model, an energy-based pharmacophore (e-pharmacophore) model and a molecular docking model, and screens a Chemdiv database by using the models step by step to obtain a compound G856-1381(4H-pyrimid [5, 4-b ]]indol-4-one，3，5-dihydro-3-(2-propen-1-yl)-2-[(2-pyridinylmethyl)thio]-) which was found to have adenosine A in vitro biological experiments1Receptor antagonistic activity and having better A1/A2AAnd (4) selectivity. Adenosine A of Compound G856-13811IC of receptor binding assay50Is 1.54. mu.M, Ki0.70 μ M; its adenosine A2AIC of receptor binding assay5047.83 μ M, Ki38.5. mu.M. Compound G856-1381 Paraadenosine A1And A2AK of receptoriThe ratio is 0.0182, which shows that the compound is adenosine A1The receptor is selective. Compound G856-1381 adenosine A1Receptor function assay (A)1IC of antaconist cAMP assay)50At 1.260. mu.M, the compound was confirmed to have a higher adenosine A1Receptor antagonistic activity.
The structure of the compound G856-1381 of the invention is shown in the attached figure 1:
g856-1381 formula: c24H21FN4O2。
G856-1381 molecular weight: 416.460.
drawings
FIG. 1 is a structural formula of compound G856-1381;
FIG. 2. Compound G856-1381 Paraadenosine A in binding assays1An inhibition curve for the receptor;
FIG. 3. Compound G856-1381 Paraadenosine A in binding assays2AAn inhibition curve for the receptor;
FIG. 4 Compound G856-13 in a functional assay81 to adenosine A1An inhibition curve for the receptor;
Detailed Description
The invention is further illustrated by the following examples for the understanding of the invention, which are not intended to limit the scope of the invention.
The present study utilized a multi-stage virtual screening technique, utilizing existing adenosine A1Constructing a random forest (random forest) by using the receptor antagonist data, and performing primary screening on a Chemdiv database by using the model; then using adenosine A1The crystal structure of the receptor (PDBID: 5N2S) is used for constructing an energy-based pharmacophore model (e-pharmacophore) and carrying out secondary screening; finally using adenosine A1The crystal structure of the receptor was subjected to a third level of screening based on molecular docking. The compounds G856-1381 obtained from the third screening were each subjected to a binding activity test (A)1/A2Abinding assay) and functional Activity assay (A)1antagonist cAMP assay)。
Test procedure for binding Activity of Compound G856-1381:
(1)A1 Binding Assay：
reagent preparation
Reaction buffer
500mL volume pH 7.4 adjusted with HCl
Name Weight Final Conc
Tris-base 3.03g 50mM
MgCl2 0.476g 10mM
EDTA 1mL 1mM
Adenosine Deaminase 500μg 1μg/mL
Washing lotion
Volume 2L, 10 Xwash to pH 7.4 with HCl
Name Weight(2L) Final Conc
Tris-base 121.14g 500mM
NaCl 180g 1.54M
By ddH2Diluting O at a ratio of 1: 10 to obtain 1X washing solution, and using.
Incubation UNIFILTER-96GF/B buffer
Name Weight ddH2O Final Conc
PEI 0.5mL 100mL 0.5％
Dilution of Compounds
a) The compounds were stored at a concentration of 20mM in DMSO and stored at-20 ℃.
b) Positive compound: DPCPX.
c) Compounds were diluted in 384 round bottom plates at 10 μ M starting concentration, 3-fold dilution, 10 points, 0.5% DMSO as negative control, 100uM DPCPX as positive control.
Positive compounds were diluted as follows:
[Required]μM [Stock](100X)mM Dilution
10 2 6μl 20mM cpd+54μL DMSO
3.33333 0.6667 20μL of 2mM cpd+40μL DMSO
1.11111 0.2222 20μL of 0.6667mM cpd+40μL DMSO
0.37037 0.0741 20μL of 0.2222mM cpd+40μL DMSO
0.12346 0.0247 20μL of 0.0741mM cpd+40μL DMSO
0.04115 0.0082 20μL of 0.0247mM cpd+40μL DMSO
0.01372 0.0027 20μL of 0.0082mM cpd+40μL DMSO
0.00457 0.0009 20μL of 0.0027mM cpd+40μL DMSO
0.00152 0.0003 20μL of 0.0009mM cpd+40μL DMSO
0.00051 0.0001 20μL of 0.0003mM cpd+40μL DMSO
negative control 40μL DMSO
Positive control 10 20μL 20mM DPCPX+20μL DMSO
250nL of diluted compound was transferred to Opti-plate, two replicates, and finally 0.5% DMSO using Echo 550.
Procedure of experiment
a) The total reaction was 50. mu.L, 250nL of compound (0.5% DMSO) was added to the Opti-plate using Echo550, and the plates were sealed with a sealing film.
b) Preparation of film, [3H ]]-mixed solution of DPCPX and reaction buffer: 0.5. mu. L A was added to each well1Membrane (1U/. mu.L) and [3H]DPCPX (final concentration 2.5nM) and 50. mu.L reaction buffer were mixed in 96-well plates with shaking at 600rpm for 5 min.
c) Incubate at 25 ℃ for 50 min.
d) UNIFILTER-96GF/B plates were treated with 0.5% PEI and 150uL of 0.5% PEI was added per well and preincubated for 1.5 hours at 4 ℃.
e) UNIFILTER-96GF/B plates were washed 2 times with Universal Harvester, 50mL each time.
f) The incubated reaction solution was transferred to a UNIFILTER-96GF/B plate, 900. mu.L of the washing solution was added to each well, and washed 4 times with a Universal Harvester, and the washed UNIFILTER-96GF/B plate was dried at 55 ℃ for 10 minutes.
g) Add 40. mu.L of ULTIMA GOLD scintillation fluid per well and read using a Top Count.
Data analysis
a)KdValues were obtained by graphipa Prism 6 software plotting.
b)IC50Obtained by analyzing the data using Xlfit 5.3.1, the X-axis is the compound concentration and the Y-axis is the CPM value.
Compound IC50The fitting curve of (2):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：Log of cpd concentration
Y：Percent inhibition(％inh)
Top and Bottom：Plateaus in same units as Y
logIC50：same log units as X
HillSlope：Slope factor or Hill slope
c)K1＝IC50/(1+(c)/Kd)
(2)A2A Binding Assay
reagent preparation
Reaction buffer
500mL volume pH 7.4 adjusted with HCl
Name Weight Final Conc
Tris-base 3.03g 50mM
MgCl2 0.476g 10mM
EDTA 1mL 1mM
Adenosine Deaminase 500μg 1μg/mL
Washing lotion
Volume 2L, 10 Xwash to pH 7.4 with HCl
Name Weight(2L) Final Conc
Tris-base 121.14g 500mM
NaCl 180g 1.54M
By ddH2Diluting O at a ratio of 1: 10 to obtain 1X washing solution, and using.
Incubation UNIFILTER-96GF/B buffer
Name Weight ddH2O Final Conc
PEI 0.5mL 100mL 0.5％
Dilution of Compounds
d) The compounds were stored at a concentration of 20mM in DMSO and stored at-20 ℃.
e) Positive compound: ZM-241385.
f) Compounds were diluted in 384 round bottom plates at 1. mu.M starting concentration, 3-fold dilution, 10 dots, 1% DMSO as a negative control, and 10uM ZM-241385 as a positive control.
Positive compounds were diluted as follows:
[Required]μM [Stock](100X)mM Dilution
1 0.1 1μl 20mM cpd+199μL DMSO
0.333333 0.0333 20μL of 30mM cpd+40μL DMSO
0.111111 0.0111 20μL of 10mM cpd+40μL DMSO
0.037037 0.0037 20μL of 3.33mM cpd+40μL DMSO
0.012346 0.00123 20μL of 1.11mM cpd+40μL DMSO
0.004115 0.00041 20μL of 0.37mM cpd+40μL DMSO
0.001372 0.000137 20μL of 0.12mM cpd+40μL DMSO
0.000457 0.000045 20μL of 0.041mM cpd+40μL DMSO
0.000152 0.000015 20μL of 0.0137mM cpd+40μL DMSO
0.00005 0.000005 20μL of 0.0046mM cpd+40μL DMSO
negative control 40μL DMSO
Positive control
1 2μL 20mM ZM-241385+38μL DMSO
transfer 5 μ L of diluted compound to 96 deep well plates, 2 replicate wells, 1% DMSO.
Procedure of experiment
a) The total reaction system was 500. mu.L, and 100. mu.L of the reaction buffer and 5. mu.L of the diluted compound (1% DMSO) were added to each well in a 96-deep well plate.
b) Preparing a mixed solution of the membrane and the reaction buffer solution: add 1. mu. L A to each well2AThe membrane (1U/. mu.L) and 300. mu.L reaction buffer were added to a 96-well plate and mixed by shaking at 600rpm for 5 min.
c) mu.L of reaction buffer and [3H ] -ZM 241385 (final concentration of 0.5nM) were added to each well and mixed by shaking at 600rpm for 5 min.
d) Incubate at 27 ℃ for 1.5 h.
e) UNIFILTER-96GF/B plates were treated with 0.5% PEI and 150uL of 0.5% PEI was added per well and preincubated for 1.5 hours at 4 ℃.
f) UNIFILTER-96GF/B plates were washed 2 times with Universal Harvester, 50mL each time.
g) The incubated reaction solution was transferred to a UNIFILTER-96GF/B plate, 900. mu.L of the washing solution was added to each well, and washed 4 times with a Universal Harvester, and the washed UNIFILTER-96GF/B plate was dried at 55 ℃ for 10 minutes.
h) Add 40. mu.L of ULTIMA GOLD scintillation fluid per well and read using a Top Count.
Data analysis
d)KdValues were obtained by graphipa Prism 6 software plotting. .
e)IC50Obtained by analyzing the data using Xlfit 5.3.1, the X-axis is the compound concentration and the Y-axis is the CPM value.
Compound IC50The fitting curve of (2):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：Log of cpd concentration
Y：Percent inhibition(％inh)
Top and Bottom：Plateaus in same units as Y
logIC50：same log units as X
HillSlope：Slope factor or Hill slope
f)K1＝IC50/(1+(c)/Kd)
compound G856-1381 functional Activity assay (A)1antadonist cAMP assay) experimental procedure:
cell culture and inoculation:
1.CHO-K1-Adenosine A1the stable cell line was cultured at 37 ℃ with 5% CO2In complete medium.
2. Experiment buffer solution: 1X HBSS, 0.1% BSA, 20mM HEPES, 100nM IBMX.
3. Cell inoculation: cells were resuspended in assay buffer and 8000 cells were seeded per well in 384-well (6007680-50, PE) assay plates.
Detection of antagonist activity of compound:
1. a8 Xworking solution of test compound (compound No. G856-1381) was prepared using the assay buffer.
2. Mu.l of 8 Xtest compound working solution was added to the 384-well test plate and incubated at 37 ℃ for 10 minutes.
3. A mixture of forskolin (8. mu.M) and NECA (40nM) was prepared with assay buffer.
4. Add 2.5. mu.l of a mixture of forskolin and NECA to the assay plate and incubate at 37 ℃ for 30 min.
5. Preparation of 20 XcAMP- d 2 and 20 Xanti-cAMP-Eu with lysis buffer3+And (3) detecting the reagent.
6. Add 10. mu.l cAMP-d2 to assay plate followed by 10. mu.l Anti-cAMP-Eu3+。
7. The test plates were incubated at room temperature for 1 hour.
8. HTRF signals at 665nm and 615nm were collected using an Envision 2104 microplate reader.
And (3) data analysis:
●Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；
●CVMax＝(SDMax/MeanMax)*100％；
●CVMin＝(SDMin/MeanMin)*100％；
●S/B＝Singal/Background；
● calculation of Compound EC Using the nonlinear fitting equation of GraphPad50/IC50：
●Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50/IC50-X)*HillSlope))
X：log of compound concentration；Y：％Activation or Inhibition％.

Claims (1)

1. Preparation of adenosine A from small molecule compound1The application of the receptor antagonist in the aspect of medicaments is that: 4H-Pyrimido [5, 4-b ]]indol-4-one，3，5-dihydro-3-(2-propen-1-yl)-2-[(2-pyridinylmethyl)thio]-，
Figure FSA0000184811270000011
CN201910547371.4A 2019-06-24 2019-06-24 A selective adenosine A1Molecules with receptor antagonistic activity Pending CN111939160A (en)

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Country Status (1)

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XU ZHEJUN等: "Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists", 《SCI CHINA CHEM》 *

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