{"content"=>"Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A adenosine receptor.", "sub"=>{"content"=>"3"}} (original) (raw)
Related papers
Chirality, 2016
The chiral separation of enantiomeric couples of three potential A 3 adenosine receptor antagonists: (R/S)-N-(6-(1-phenylethoxy)-2-(propylthio)pyrimidin-4-yl)acetamide (1), (R/ S)-N-(2-(1-phenylethylthio)-6-propoxypyrimidin-4-yl)acetamide (2), and (R/S)-N-(2-(benzylthio)-6-sec-butoxypyrimidin-4-yl)acetamide (3) was achieved by high-performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434-440, 2016.
Journal of medicinal …, 2009
To further investigate new potent and selective human A 1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy-and 5′-(2-fluorophenylthio)-5′-deoxy-N 6 -cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In the series of N 6 -cyclopentyl-and N 6 -(endo-norborn-2-yl)adenosine derivatives, 5′-chloro-5′-deoxy-CPA (1) and 5′-chloro-5′-deoxy-(()-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA 1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA 1 AR vs hA 3 AR compared to that of the parent 5′-hydroxy compounds CPA and (()-ENBA was rationalized by a molecular modeling analysis. 5′-Chloro-5′-deoxy-(()-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p. D-ribofuranosyl)purine (15), prepared as reported by Hou et al., 7 with (()-endo-norborn-2-yl-amine hydrochloride in the presence of triethylamine in absolute ethanol, followed by sugar deblocking with methanolic ammonia, gave 2-Cl-(()-ENBA (16). Compound 16 was protected as 2′,3′-isopropylidene derivative 17 using camphorsulfonic acid and 2,2-dimethoxypropane in acetone in 80% yield. Conversion of 17 to 5′-chloro derivative 18 was performed by treatment with a mixture of thionyl chloride, pyridine, and acetonitrile. Finally, deprotection of 18 with 70% formic acid at 40°C furnished compound 4. Direct conversion of 2-Cl-(()-ENBA (16) into its 5′-chloro-5′-deoxy derivative 4 using thionyl chloride and pyridine in acetonitrile or thionyl chloride and hexamethylphosphoramide (HMPA) was also tried, but low yields of 4 were obtained.
Comparative molecular field analysis of selective A< sub> 3 adenosine receptor agonists
1995
A series of 48 Ne-benzyladenosine 5'-umnamide derivatives has been described recently as moderately selective A 3 adenosine receptor agonists of nanomolar potency (Gallo-Rodriguez, C. et al. J. Med. Chem. 1994, 37, 636). Quantitative structure activity relationships in this series, including some novel derivatives, have been investigated using a Comparative Molecular Field Analysis (CoMFA), with emphasis on the AP-substituent. The resulting three dimensional pharmacophore model defines the steric and electronic factors which modulate in vitro affinities in binding to rat brain A 3 adenosine receptors. The model indicates a positive correlation of affinity with the steric characteristics of the compounds (major factor), particularly toward the 3-position of the benzyl ring of ~-benzyl NECA, and a weak correlation with the electrostatic effects of the AS-substituent. A comparison of active and inactive compounds using volume maps showed that bulk at the 3-position of the benzyl ring of the molecule is conducive to high affinity at A 3 receptors, while steric bulk at other positions of the benzyl ring leads to poor binding, t-Boc-amino acid conjugates of a 3-aminobenzyl derivative were synthesized to probe the steric and hydrophobic limitations at that position. We have discovered a subregion of the/~benzyl binding pocket occupied by a 3-(L-prolylamino) group that is sterically disallowed at A 3 receptors and allowed in A t and A,. receptors. 6-N-Phenylhydrazino and 6-O-phenylhydroxylamino derivatives, incorporating major changes in electrostatic character of the ligand proximal to the purine, were predicted by the CoMFA model to have high A 3 affinity. Such analogs were synthesized and found to be well tolerated at the A 3 receptor binding site.
Journal of Medicinal Chemistry, 2014
We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A 1 receptor (hA 1 AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target receptor. They show a very diverse range of kinetic profiles (from 1 min (compound 52) to 1 h (compound 43)), and their structure−affinity relationships (SAR) and structure−kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics. ■ RESULTS AND DISCUSSION Design and Synthesis. The S-substituted thiopyrimidines were all synthesized in a two-step procedure consisting of (i)
Journal of Medicinal Chemistry, 2009
To further investigate new potent and selective human A 1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy-and 5′-(2-fluorophenylthio)-5′-deoxy-N 6 -cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In the series of N 6 -cyclopentyl-and N 6 -(endo-norborn-2-yl)adenosine derivatives, 5′-chloro-5′-deoxy-CPA (1) and 5′-chloro-5′-deoxy-(()-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA 1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA 1 AR vs hA 3 AR compared to that of the parent 5′-hydroxy compounds CPA and (()-ENBA was rationalized by a molecular modeling analysis. 5′-Chloro-5′-deoxy-(()-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p. D-ribofuranosyl)purine (15), prepared as reported by Hou et al., 7 with (()-endo-norborn-2-yl-amine hydrochloride in the presence of triethylamine in absolute ethanol, followed by sugar deblocking with methanolic ammonia, gave 2-Cl-(()-ENBA (16). Compound 16 was protected as 2′,3′-isopropylidene derivative 17 using camphorsulfonic acid and 2,2-dimethoxypropane in acetone in 80% yield. Conversion of 17 to 5′-chloro derivative 18 was performed by treatment with a mixture of thionyl chloride, pyridine, and acetonitrile. Finally, deprotection of 18 with 70% formic acid at 40°C furnished compound 4. Direct conversion of 2-Cl-(()-ENBA (16) into its 5′-chloro-5′-deoxy derivative 4 using thionyl chloride and pyridine in acetonitrile or thionyl chloride and hexamethylphosphoramide (HMPA) was also tried, but low yields of 4 were obtained.
2011
interaction model proposed by Liljefors and B0ges0, extending this model to include the important benzamide class of DA D-2 receptor antagonists. For benzamides with an acyclic amide side chain, the most probable receptorbound conformation is the one with an extended alkyl substituent. The enantioselectivity of the chirat benzamide of type 3 may be rationalized in terms of conformational energy differences for the receptor bound enantiomers. The N-alkyl substituent of the benzamides is proposed to be able to interact with two different sites for the N-alkyl substituent. For the benzamides studied in this work, the N-benzyl groups of compounds 6 and 12 are proposed to interact with one receptor site, while the alkyl group in benzamides with a N-ethyl group (compounds 9, 10, and 11) may interact with the other site.
In this study, we determined the crystal structure of an engineered human adenosine A 2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.
Bioorganic & Medicinal Chemistry Letters, 2008
On the basis of potent and selective A 3 adenosine receptor (AR) antagonist, 2-chloro-N 6 -(3-iodobenzyl)-4 0 -thioadenosine-5 0 -N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5 0 -N,N-dialkyluronamide derivatives, synthesized from D D-gulonic c-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5 0 -uronamide was essential for the pure A 3 AR antagonism. 5 0 -N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5 0 -N,N-dialkyl or 5 0 -N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A 3 AR. A N 6 -(3-bromobenzyl) derivative 6c (K i = 9.32 nM) exhibited the highest binding affinity at the human A 3 AR with very low binding affinities to other AR subtypes.
Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines
European Journal of Medicinal Chemistry, 2008
A new series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones (4aek) have been synthesized through a facile cyclization reaction of 4-hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidines (3aek) using carbon disulphide under basic conditions. 4-Hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (3aek) were prepared by replacing the chloro group of 4-chloro-2-substituted-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (2aek) with hydrazine hydrate which were obtained by a known one-pot synthesis. The affinities of these compounds for adenosine A 1 /A 2A receptors were determined at 1 mM concentration. The test compounds which exhibited more than 20% inhibition were selected and further screened at six different concentration levels to estimate their EC 50 /K i values. The most potent compounds in the series were 4c and 4d having an ethyl side chain at C 5 position with dimethyl and cyclohexyl substitution at the C 8 eC 9 positions, exhibiting K i values of 2.1 and 1.1 mM, respectively, at A 1 ARs. The SAR indicates that by increasing or decreasing the alkyl chain length at C 5 led to reduced affinity. The remaining aryl/arylalkyl derivatives of the series were inactive showing that a simple alkyl side chain at C 5 is necessary for these ligands to bind at A 1 ARs. However, none of the compounds showed inhibition on A 2A receptors at 1 mM concentration indicating their selectivity. This communication describes the design, synthesis and evaluation of these new molecules.
Bioorganic & medicinal …, 2008
A series of 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -C-methyl analogues of the A 1 adenosine receptor (A 1 AR) full agonists N 6 -cyclopentyladenosine (CPA), 2-chloro-N 6 -cyclopentyladenosine (CCPA), N 6 -[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N 6 -cyclopentylamino series, the 5 0 -substituted derivatives showed a reduced affinity at the bovine A 1 AR compared to the parent compounds; however, the selectivity for A 1 versus A 2A receptor was retained or increased. The corresponding N 6 -3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A 1 AR. The 5 0 -methylthionocarbamoyl derivative of 2 0 -Me-CCPA showed the best affinity at porcine A 1 AR with a K i value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3-to 5-fold lower affinity at A 1 AR and very low affinity at the other subtypes (A 2A , A 2B , and A 3 ) compared to the corresponding N 6 -cyclopentyl analogues. The 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A 1 agonists at the porcine receptor. Docking studies explained the lower affinity of N 6 -3-(R)-tetrahydrofuranyl-substituted compounds at bovine A 1 AR compared to that of N 6 -cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2 0 -C-methyl-N 6 -3-(R)-tetrahydrofuranyl adenosine analogues at human A 1 AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).