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1.
Eur J Med Chem ; 113: 11-27, 2016 May 04.
Article in English | MEDLINE | ID: mdl-26922225

ABSTRACT

CB2 cannabinoid receptor ligands are known to be therapeutically important for the treatment of numerous diseases. Recently, we have identified the heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives as highly potent and selective CB2 receptor ligands, showing that the pharmakodynamics of the new compounds was controlled by the nature of the heterocycle core. In this paper we describe the synthesis and biological evaluation of 7-oxo-4-pentyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives that led to the identification of novel CB2 receptor inverse agonists. Cyclic AMP experiments on CB2 receptors expressed in CHO cells revealed that introduction of structural modifications at position 2 of triazolopyrimidine template changes the functional activity from partial to inverse agonism. The molecular docking analysis of the novel structures is reported.


Subject(s)
Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Triazoles/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
2.
J Med Chem ; 58(13): 5355-60, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26046697

ABSTRACT

In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR antagonists.


Subject(s)
Drug Design , Purinergic P1 Receptor Antagonists/chemistry , Purinergic P1 Receptor Antagonists/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemistry , Receptor, Adenosine A3/chemistry , Animals , Binding, Competitive , CHO Cells , Cricetulus , Cyclic AMP/metabolism , Humans , Models, Molecular , Molecular Structure , Radioligand Assay , Structure-Activity Relationship
3.
Eur J Med Chem ; 97: 289-305, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-26002335

ABSTRACT

Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrazoles/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
4.
Pharm Pat Anal ; 4(2): 75-94, 2015.
Article in English | MEDLINE | ID: mdl-25853468

ABSTRACT

The transient receptor potential ankyrin 1 (TRPA1) channel is an irritant sensor highly expressed on nociceptive neurons. The clinical use of TRPA1 antagonists is based on the concept that TRPA1 is active during disease states like neuropathic pain. Indeed, in Phase 2a proof-of-concept studies the TRPA1 antagonist GRC17536 has shown efficacy in patients with painful diabetic neuropathy. Moreover, animal studies suggest that the therapeutic value of TRPA1 antagonists extends beyond pain to pruritus, asthma and cough with limited safety concerns. This review provides a comprehensive overview of the patent literature (since 2007) on small-molecule inhibitors of the TRPA1 channel. Despite the clear progress, many unanswered questions remain. Future advancement to Phase 3 studies will assess the real translational potential of this research field.


Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Transient Receptor Potential Channels/antagonists & inhibitors , Animals , Calcium Channels , Drug Discovery , Drug Industry , Humans , Patents as Topic , TRPA1 Cation Channel
5.
J Med Chem ; 58(7): 3253-67, 2015 Apr 09.
Article in English | MEDLINE | ID: mdl-25780876

ABSTRACT

Stimulation of A2A adenosine receptors (AR) promotes anti-inflammatory responses in animal models of allergic rhinitis, asthma, chronic obstructive pulmonary disease, and rheumatic diseases. Herein we describe the results of a research program aimed at identifying potent and selective agonists of the A2AAR as potential anti-inflammatory agents. The recent crystallographic analysis of A2AAR agonists and antagonists in complex with the receptor provided key information on the structural determinants leading to receptor activation or blocking. In light of this, we designed a new series of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5'-N-ethylcarboxamidoadenosines with high A2AAR affinity, activation potency and selectivity obtained by merging distinctive structural elements of known agonists and antagonists of the investigated target. Docking-based SAR optimization allowed us to identify compound 42 as one of the most potent and selective A2A agonist discovered so far (Ki hA2AAR = 4.8 nM, EC50 hA2AAR = 4.9 nM, Ki hA1AR > 10 000 nM, Ki hA3AR = 1487 nM, EC50 hA2BAR > 10 000 nM).


Subject(s)
Adenosine A2 Receptor Agonists/chemistry , Adenosine A2 Receptor Agonists/pharmacology , Receptor, Adenosine A2A/chemistry , Adenosine A2 Receptor Agonists/chemical synthesis , Adenosine A2 Receptor Agonists/metabolism , Adenosine-5'-(N-ethylcarboxamide)/chemistry , Animals , CHO Cells/drug effects , Chemistry Techniques, Synthetic , Cricetulus , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship
6.
Med Chem ; 11(4): 342-53, 2015.
Article in English | MEDLINE | ID: mdl-25494808

ABSTRACT

A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIß binding sites in the DNA binding interface were performed.


Subject(s)
Antineoplastic Agents/chemical synthesis , DNA-Binding Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridones/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , DNA/antagonists & inhibitors , DNA/chemistry , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Etoposide/pharmacology , Humans , Molecular Docking Simulation , Pyrazoles/pharmacology , Pyridones/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology
7.
J Med Chem ; 57(18): 7673-86, 2014 Sep 25.
Article in English | MEDLINE | ID: mdl-25181013

ABSTRACT

A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.


Subject(s)
Adenosine A1 Receptor Agonists/chemical synthesis , Adenosine A1 Receptor Agonists/pharmacology , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A1/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Adenosine A1 Receptor Agonists/chemistry , Allosteric Regulation/drug effects , Animals , CHO Cells , Chemistry Techniques, Synthetic , Cricetinae , Cricetulus , Humans , Kinetics , Thiophenes/chemistry
8.
Bioorg Med Chem ; 22(1): 148-66, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24332652

ABSTRACT

2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.


Subject(s)
Receptor, Adenosine A1/metabolism , Thiophenes/chemical synthesis , Thiophenes/metabolism , Allosteric Regulation , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Structure-Activity Relationship , Thiophenes/chemistry
9.
J Med Chem ; 56(11): 4482-96, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-23697626

ABSTRACT

We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB2 receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo[3,4-b]pyridines. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.


Subject(s)
Amides/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, Cannabinoid, CB2/metabolism , Amides/chemistry , Amides/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Drug Inverse Agonism , Humans , Male , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Structure-Activity Relationship
10.
Pain ; 154(6): 864-73, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23518609

ABSTRACT

Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.


Subject(s)
Chronic Pain/drug therapy , Diabetic Neuropathies/drug therapy , Hyperalgesia/drug therapy , Inflammation/drug therapy , Musculoskeletal Pain/drug therapy , Oxazines/agonists , Quinolones/agonists , Receptor, Cannabinoid, CB2/agonists , Animals , Behavior, Animal/drug effects , Chronic Pain/metabolism , Diabetic Neuropathies/metabolism , Dose-Response Relationship, Drug , Female , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Humans , Hyperalgesia/metabolism , Inflammation/metabolism , Male , Mice , Motor Activity/drug effects , Musculoskeletal Pain/metabolism , NF-kappa B/metabolism , Pain Measurement , Rats , Rats, Sprague-Dawley , Rotarod Performance Test , Treatment Outcome
11.
J Med Chem ; 56(3): 1098-112, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-23350768

ABSTRACT

Recent developments indicate that CB(2) receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB(2) receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB(2) receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists.


Subject(s)
Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Animals , Drug Design , Humans , Magnetic Resonance Spectroscopy , Male , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
12.
J Med Chem ; 55(14): 6608-23, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22738271

ABSTRACT

Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB(2) receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB(2)K(i) = 2.5 nM, SI = 166; 21, hCB(2)K(i) = 0.81 nM, SI = 383; 38, hCB(2)K(i) = 15.8 nM, SI > 633; 56, hCB(2)K(i) = 8.12 nM, SI > 1231; (R)-58, hCB(2)K(i) = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (R)-enantiomers exhibited greater affinity at the CB(2) receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB(2) receptor.


Subject(s)
Quinolines/metabolism , Quinolines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Quinolines/chemical synthesis , Quinolines/chemistry , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Substrate Specificity
13.
J Med Chem ; 55(11): 5380-90, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22568637

ABSTRACT

A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C(5) position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K(i)(hA(3)) = 9.7 nM, IC(50)(hA(3)) = 30 nM, K(i)(hA(1)/hA(3)) = 351, K(i)(hA(2A)/hA(3)) > 515, IC(50)(hA(2B)) > 5 µM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.


Subject(s)
Adenosine A3 Receptor Antagonists/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptor, Adenosine A3/metabolism , Urea/analogs & derivatives , Adenosine A3 Receptor Antagonists/chemistry , Adenosine A3 Receptor Antagonists/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Models, Molecular , Radioligand Assay , Solubility , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacology , Water
14.
Bioorg Med Chem ; 20(5): 1690-8, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22325155

ABSTRACT

The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N(7)-phenylacetamide or N(7)-[4-(substituted-phenyl)-thiazol-2-yl]-acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC(50)=400nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain.


Subject(s)
Analgesics/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Nerve Tissue Proteins/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Transient Receptor Potential Channels/antagonists & inhibitors , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Calcium Channels , Humans , Inflammation/drug therapy , Male , Pain/drug therapy , Pyrimidines/chemical synthesis , Rats , Rats, Sprague-Dawley , TRPA1 Cation Channel
15.
Bioorg Med Chem ; 20(2): 1046-59, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22204739

ABSTRACT

The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors.


Subject(s)
Purinergic P1 Receptor Antagonists/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Triazoles/chemistry , Humans , Protein Binding/drug effects , Purinergic P1 Receptor Antagonists/chemical synthesis , Purinergic P1 Receptor Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A3/chemistry , Receptor, Adenosine A3/metabolism , Structure-Activity Relationship
16.
J Med Chem ; 55(2): 797-811, 2012 Jan 26.
Article in English | MEDLINE | ID: mdl-22148859

ABSTRACT

Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A(2B) adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A(2B) adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A(2B)AR, a new series of compounds was synthesized and evaluated in binding studies against the human A(1), A(2A), A(3), and A(2B)ARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A(2B) receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: K(i) A(2B) = 9.4 nM, IC(50) hA(2B) = 26 nM hA(1)/hA(2B) = 269, hA(2A)/hA(2B) > 106, hA(3)/hA(2B) >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A(2B)AR with good selectivity over AR subtypes (K(i) = 4.0 nM, IC(50) hA(2B) = 20 nM hA(1)/hA(2B) = 183, hA(2A),hA(3)/hA(2B) > 250).


Subject(s)
Adenosine A2 Receptor Antagonists/chemical synthesis , Benzimidazoles/chemical synthesis , Models, Molecular , Pyrazoles/chemical synthesis , Quantitative Structure-Activity Relationship , Receptor, Adenosine A2B/metabolism , Xanthines/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Humans , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Xanthines/chemistry , Xanthines/pharmacology
17.
J Med Chem ; 54(14): 5205-20, 2011 Jul 28.
Article in English | MEDLINE | ID: mdl-21675777

ABSTRACT

A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A(1), A(2A), and A(3) adenosine receptors. Efficacy at the hA(2B) AR and antagonism of selected ligands at the hA(3) AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA(3) AR (K(i) values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A(1), A(2A), and A(2B) AR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K(i) hA(3) = 1.46 nM, K(i) hA(2A)/K(i) hA(3) > 3425; IC(50) hA(2B)/K(i) hA(3) > 3425; K(i) hA(1)/K(i) hA(3) = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands.


Subject(s)
Adenosine A3 Receptor Antagonists/chemical synthesis , Purines/chemical synthesis , Receptor, Adenosine A3/metabolism , Adenosine A3 Receptor Antagonists/chemistry , Adenosine A3 Receptor Antagonists/pharmacology , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Purines/chemistry , Purines/pharmacology , Radioligand Assay , Receptor, Adenosine A2B/genetics , Receptor, Adenosine A2B/metabolism , Receptor, Adenosine A3/chemistry , Receptor, Adenosine A3/genetics , Sequence Alignment , Stereoisomerism , Structure-Activity Relationship , Transfection
18.
Bioorg Med Chem ; 16(24): 10281-94, 2008 Dec 15.
Article in English | MEDLINE | ID: mdl-19006671

ABSTRACT

We recently described the synthesis of 1-benzyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-diones, new potent and selective A(3) adenosine receptor antagonists containing a xanthine core. The present work can be considered an extension of our SAR studies on related structures in which the effect of different kind of substitutions at the 1-, 3- and 8-positions has been evaluated in order to improve both the potency and the hydrophilicity of the originally synthesised molecules. The A(3) binding disposition of these compounds was also investigated through docking and 3D-QSAR studies.


Subject(s)
Adenosine A3 Receptor Antagonists , Purinones/chemical synthesis , Purinones/pharmacology , Animals , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Cricetulus , Data Interpretation, Statistical , Molecular Structure , Purinones/chemistry , Quantitative Structure-Activity Relationship , Receptor, Adenosine A3/metabolism
19.
Bioorg Med Chem ; 16(5): 2419-30, 2008 Mar 01.
Article in English | MEDLINE | ID: mdl-18077171

ABSTRACT

A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A(2B) adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A(2B), A(1), A(2A), and A(3) adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A(2B) adenosine receptor K(i)=7nM and good selectivity (A(1), A(2A), A(3)/A(2B)>140). Synthesis and SAR of this novel class of compounds is presented herein.


Subject(s)
Adenosine A2 Receptor Antagonists , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptor, Adenosine A2B/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Pyrazoles/chemistry , Structure-Activity Relationship , Xanthines/chemistry
20.
Bioorg Med Chem ; 15(7): 2514-27, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17306548

ABSTRACT

A new series of N(6)-[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5'-N-ethylcarboxamido-adenosines (24-43) has been synthesised and tested in binding assays at hA(1), hA(2A) and hA(3) adenosine receptors, and in a functional assay at the hA(2B) subtype. The examined compounds displayed high potency in activating A(2B) receptors with good selectivity versus A(2A) subtypes. The introduction of an unsubstituted 4-[(phenylcarbamoyl)-methoxy]-phenyl chain at the N(6) position of 5'-N-ethylcarboxamido-adenosine led us to the recognition of compound 24 as a full agonist displaying the highest efficacy of the series (EC(50) hA(2B)=7.3 nM). These compounds represent the first report about adenosine-related structures capable of activating hA(2B) subtype in the low nanomolar range.


Subject(s)
Adenosine A2 Receptor Agonists , Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Adenosine/pharmacology , Carbamates/chemical synthesis , Carbamates/pharmacology , Animals , CHO Cells , Computer Simulation , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Humans , Indicators and Reagents , Kinetics , Magnetic Resonance Spectroscopy , Radioligand Assay
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