In the last few years the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) scaffold was investigated in order to obtain potent and selective adenosine receptor (AR) antagonists.1 In particular, A2B ARs appear to be involved in the regulation of mast cell secretion, diabetes, intestinal functions, angiogenesis, sickling and haemolysis of red blood cells, so antagonists for this receptor subtype are suitable in treatment of asthma, secretory diarrhoea, cancer and sickle cell disease.2 Unfortunately none of the PTPs synthetized so far, bearing a C2-furyl ring and various substituents at the N7, N8 and N5 positions, showed both affinity and selectivity for the A2B subtype.1 A PTP derivative that displays good affinity for the A2B ARs (Ki=11.5 nM) is compound 1, but it still retains greater affinity at the hA3 receptors (Ki=1.2 nM). For these reasons we decided to focus our attention on the position 2. Since it has been demonstrated that the furan ring is not essential for the receptor recognition, we decided to replace it with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole-4-yl residue present in the CVT 6975 (2), one of the most potent xanthine A2B adenosine receptor antagonist,3 with the aim of deeply exploring the role of this position and possibly obtaining good A2B antagonists. Concerning the N5 position, we maintain substituents similar to that present in compound 1, which gives good affinity at the A2B AR. In particular, arylcarbamoyl and arylacetyl moieties were introduced and their activity will be compared to that of N5-unsubstituted derivative. Unfortunately, none of the PTPs synthetized in this series (3-7) showed activity at the A2B adenosine receptors, but surprisingly still have good affinity, in the nanomolar range, versus the human A3 receptor subtype. The substitution at the N5 position seems to affect the affinity at the A3 adenosine receptors more then the substituent in the C2 position. In fact, the N5-unsubstituted derivative is almost inactive at all four adenosine receptors. Instead, the best compound of this series is the 5-phenylacetamido derivative which showed a Ki value of 11.1 nM at the A3 AR and high selectivity versus the other receptor subtypes. References 1. Baraldi, P.G., et al., 2002. Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: A possible template for adenosine receptor subtypes? Current Pharm Des 8: 2299-2332. 2. Feoktistov, I., et al., 1998. Adenosine A2B receptors as therapeutic targets. Drug Dev Res 45: 198-206. 3. Kalla, R., et al., 2006. Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: high affinity and selective A2B adenosine receptor antagonists. J Med Chem 49:3682–3692.

CVT 6975-like Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives: an Attempt towards A2B Adenosine Receptor Affinity.

REDENTI, SARA;FEDERICO, STEPHANIE;MORO, STEFANO;SPALLUTO, GIAMPIERO
2014-01-01

Abstract

In the last few years the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) scaffold was investigated in order to obtain potent and selective adenosine receptor (AR) antagonists.1 In particular, A2B ARs appear to be involved in the regulation of mast cell secretion, diabetes, intestinal functions, angiogenesis, sickling and haemolysis of red blood cells, so antagonists for this receptor subtype are suitable in treatment of asthma, secretory diarrhoea, cancer and sickle cell disease.2 Unfortunately none of the PTPs synthetized so far, bearing a C2-furyl ring and various substituents at the N7, N8 and N5 positions, showed both affinity and selectivity for the A2B subtype.1 A PTP derivative that displays good affinity for the A2B ARs (Ki=11.5 nM) is compound 1, but it still retains greater affinity at the hA3 receptors (Ki=1.2 nM). For these reasons we decided to focus our attention on the position 2. Since it has been demonstrated that the furan ring is not essential for the receptor recognition, we decided to replace it with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole-4-yl residue present in the CVT 6975 (2), one of the most potent xanthine A2B adenosine receptor antagonist,3 with the aim of deeply exploring the role of this position and possibly obtaining good A2B antagonists. Concerning the N5 position, we maintain substituents similar to that present in compound 1, which gives good affinity at the A2B AR. In particular, arylcarbamoyl and arylacetyl moieties were introduced and their activity will be compared to that of N5-unsubstituted derivative. Unfortunately, none of the PTPs synthetized in this series (3-7) showed activity at the A2B adenosine receptors, but surprisingly still have good affinity, in the nanomolar range, versus the human A3 receptor subtype. The substitution at the N5 position seems to affect the affinity at the A3 adenosine receptors more then the substituent in the C2 position. In fact, the N5-unsubstituted derivative is almost inactive at all four adenosine receptors. Instead, the best compound of this series is the 5-phenylacetamido derivative which showed a Ki value of 11.1 nM at the A3 AR and high selectivity versus the other receptor subtypes. References 1. Baraldi, P.G., et al., 2002. Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: A possible template for adenosine receptor subtypes? Current Pharm Des 8: 2299-2332. 2. Feoktistov, I., et al., 1998. Adenosine A2B receptors as therapeutic targets. Drug Dev Res 45: 198-206. 3. Kalla, R., et al., 2006. Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: high affinity and selective A2B adenosine receptor antagonists. J Med Chem 49:3682–3692.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2835202
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