Antiangiogenic agents: an update on small molecule VEGFR inhibitors.

Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.

2-Amino/azido/hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines: synthesis and pharmacological evaluation.

New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the chemical modulation of the substituent in position 2 of the scaffold, with the aim to produce analgesic/antiphlogistic agents more potent than analogues previously reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing test; the analgesic doses of the compounds did not affect mice spontaneous locomotor activity thus any confounding sedative effect could be excluded. These derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced platelet aggregation, probably due to a strong, non selective, inhibition of cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the compounds did not cause gastric damage in rats after acute oral administration. A different pharmacological profile was observed for the 2-azido derivatives, particularly in vivo.

New pyrazolo[3,4-d]pyrimidines endowed with A431 antiproliferative activity and inhibitory properties of Src phosphorylation.

New 4-aminopyrazolo[3,4-d]pyrimidines bearing various substituents at the position 1 and 6, were synthesized. The new compounds showed antiproliferative activity toward A431 cells, were found to be inhibitors of Src phosphorylation, and induced apoptotic cell death. In particular, 2h was a better inhibitor of Src phosphorylation than the reference compound PP2.

N-Acyl-N-phenyl ureas of piperidine and substituted piperidines endowed with anti-inflammatory and anti-proliferative activities.

Six series of N-acyl-N-phenyl ureas 1-6 of piperidine (1), and 2-ethyl- (2), 3-methyl- (3), 4-methyl- (4), 4-phenyl- (5), cis-2,6-dimethyl- (6) piperidine were synthesised and evaluated for their anti-inflammatory, anaesthetic, anti-pyretic properties. Some derivatives of series 1 and 5 were also assayed for anti-proliferative activity. Several compounds showed an anti-inflammatory activity comparable or slighty inferior to that of indomethacin in rats (1c,d, 2a,b,g,h, 3b, 4h, 5d,e). Moreover, an appreciable anti-inflammatory activity was also found in 2c,e, 3e,f,g, 4g, 5a,b,c,f,h, and 6a,b,d. All the compounds were devoid of anti-pyretic activity and only a few of them exhibited a low level of infiltration anaesthesia in mice. Compound 5a showed a broad spectrum anti-cancer activity (at low micromolar concentrations), particulary significant against leukemia subpanel.

Synthesis and biological data of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters, a new series of A1-adenosine receptor (A1AR) ligands.

The synthesis of a new family of A1-adenosine receptor (A1AR) ligands 3a-n has been performed in a straightforward way. Affinity data at A1AR, A2AAR and A3AR in bovine membranes show that these new compounds bind the A1AR in a selective way over A2AAR and A3AR and one of them (3j) presents a very high affinity, probably due to the phenethylamine substituent at C-4.

3-Arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones as anti-inflammatory and analgesic agents.

Two series of 3-arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones 2 with potential anti-inflammatory and analgesic activity were prepared and tested. Pharmacological results revealed that all the title compounds, endowed with an arylsulphonyl side chain, possess good antalgic activity and fair anti-inflammatory properties. The analgesic profile of the two series, evaluated by the acetic acid writhing test, showed that compounds 2c, 2f and 2h, in particular, were the most active. Structure-activity relationships are briefly discussed.

Synthesis and pharmacological evaluation of 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines endowed with in vitro antiplatelet activity.

A series of new 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines 3a-i have been synthesized and tested in vivo for the anti-inflammatory/analgesic/antipyretic effects and in vitro to evaluate the antiplatelet activity on guinea-pig platelet-rich plasma aggregated by collagen, adenosine-5'-diphosphate (ADP) and arachidonic acid (AA). Title compounds were ineffective in vivo; however, the pyrrolidino derivatives 3a and 3c exhibited an antiplatelet activity against all the aggregants differing from that of acetylsalicylic acid (ASA) while the 5-morpholino derivatives 3g-i showed the most potent ASA-like antiplatelet activity.

New polycyclic pyrimidine derivatives with antiplatelet in vitro activity: synthesis and pharmacological screening.

The preparation and the pharmacological screening of novel anti-aggregatory/antiphlogistic polycyclic pyrimidine derivatives are described. The compounds were developed starting from bioactive 2-aminobenzopyranopyrimidine derivatives in order to assess the importance of the benzopyrano[4,3-d]pyrimidine structure and the role of an amino basic moiety in position 2. Antiplatelet activity was assessed in vitro against ADP and arachidonic acid-induced aggregation in guinea-pig plasma. Anti-inflammatory/analgesic/antipyretic activities were studied in rat paw oedema, mouse writhing test and E. coli-induced rat fever. Ulcerogenic and gastroprotective effects were also investigated in vivo on rat gastric mucosa. Among the tested compounds, the 5-substituted benzopyranopyrimidine derivatives 3d and 4d proved to be the most active antiplatelet agents as potent as acetylsalicylic acid against arachidonic acid-stimulated aggregation. Furthermore the 2-methylthio derivative 4d was endowed with greater efficacy against ADP aggregation suggesting that additional non-TXA2 dependent mechanisms are involved in its biological activity. Orally administered at 100 mg kg(-1) in rats this latter compound displayed antiphlogistic acitivity comparable to indomethacin (10 mg kg(-1)) coupled with an unusual gastroprotective effect on ethanol-induced ulcers. In conclusion, these findings indicate that the 5-pyrrolidino-2-methylthiobenzopyrano[4,3-d]pyrimidine 4d fulfils the chemical requirements to exhibit antiplatelet activity associated with gastroprotective effect.

N-substituted 3-(arylamino)-4,5-dihydro-2H-benz[g]indazol-2-yl acetamides with anti-inflammatory and analgesic activities.

A series of substituted 3-(arylamino)-4,5-dihydro-2H-benz[g]indazol-2-yl acetamides was synthesized and tested in comparison with former analogues. The title compounds showed only weak antiarrhythmic properties but good anti-inflammatory and antinociceptive activity, particularly evident in the morpholino derivative.

O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one oxime (camphor oxime) with analgesic and antiarrhythmic activities.

A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents.

Antiinflammatory agents: new series of N-substituted amino acids with complex pyrimidine structures endowed with antiphlogistic activity.

A series of N-methyl-N-pyrimidin-2-yl glycines 2a-e, having the pyrimidine ring fused with a cyclohexane [N-methyl-N-(5,6,7,8-tetrahydroquinazolin-2-yl)glycine], cyclohexene [N-methyl-N-(5,6-dihydroquinazolin-2-yl)glycine], 1,2,3,4-tetrahydronaphthalene [N-methyl-N-(5,6-dihydrobenzo[e]quinazolin-2-yl)glycine], benzopyrane [N-methyl-N-(5-phenyl-5H-[1]benzopyrano[4,3-d]pyrimidin-2-yl)glyci ne] and benzothiopyrane [N-methyl-N-(5H-[1]benzothiopyrano[4,3-d]pyrimidin-2-yl)glycine] ring, was prepared and tested for antiinflammatory activity. With the same purpose a number of N-5H-[1]benzopyrano[4,3-d]pyrimidin-2-yl substituted amino acids 3a-e, having a different chain length and branching were also synthesized and tested. All the described products 2 and 3 showed an appreciable antiphlogistic activity, particularly 2b and 2c.

Synthesis and anti-inflammatory activity of esters derived from 5-aryl-1,2-dihydro-2-(2-hydroxyethyl)-3H-1,2,4-triazole-3-thiones.

Some aliphatic and aromatic esters 2a-l were prepared starting from 5-aryl-1,2,4-triazoline-3-thiones bearing a 2-hydroxyethyl chain in position 2. The title compounds were evaluated for antipyretic and anti-inflammatory activities. Nearly all derivatives and in particular 2f, 2h, 2k exhibited antiphlogistic properties but were lacking in antipyretic activity.

Preparation of new 5-aroylamino substituted 3-nicotinoyl/isonicotinoyl-1,3,4-thiadiazol-2(3H)-ones with anti-inflammatory activity.

A series of 1,3,4-thiadiazol-2(3H)-ones (2a-j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position 5 of the ring was prepared and evaluated for antipyretic and anti-inflammatory activities. All the title compounds and in particular 2e, 2i and 2j exhibited anti-inflammatory activity and were devoid of antipyretic properties.

Synthesis of 6-thiosubstituted 5-ethoxycarbonyl-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones, 6-substituted 5-hydroxy-1,3-diphenyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones and their esters with local anesthetic, antiarrhythmic, antiinflammatory and analgesic activities.

The synthesis of 6-thiosubstituted 5-ethoxycarbonyl-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin- 4(1H)-ones 3, and of 6-substituted 5-hydroxy-1,3-diphenyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 5 and their esters 6 is described. These derivatives were prepared in order to evaluate the influence on the pharmacological profile of alkyl substituents bearing polar/hydrophilic functionalities at an enethiol substructure as in compounds 3 or to assess the effects arising from the incorporation of the sulfur atom in a thiophene moiety as in thienopyrimidinones 5 and 6 in comparison with a series of 5-substituted 6-acylthio-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones 1c,d, previously described. Preliminary screenings suggest that all tested compounds maintained or even increased the local anesthetic activity, but failed in the platelet antiaggregating activity; on the other hand, antiarrhythmic and antiinflammatory activity was preserved in some esters 6.

N-arylsubstituted-1-aryl-3,4-diphenyl-5-pyrazole amines with analgesic and antiarrhythmic properties.

A series of N-aryl substituted-1-aryl-3,4-diphenyl-5-pyrazole amines was synthesized and evaluated for antiinflammatory, antihypertensive and platelet antiaggregating activities. Several of them were found to exhibit a significant analgesic and antiarrhythmic activity.

2-Aryl-6-methyl-3-phenylamino-6,7-dihydropyrano[4,3-c]pyrazol-4(2H)-ones with analgesic activity.

A series of 2-aryl-6-methyl-3-phenylamino-6,7-dihydropyrano[4,3-c]pyrazol-4(2H )-ones were prepared and tested for antiinflammatory, analgesic, antipyretic, antiarrhythmic, antihypertensive and platelet antiaggregating activities. All of them showed an appreciable level of analgesic activity in mice.

Synthesis and pharmacological profile of novel N-substituted N-[5H-[1]benzopyrano[4,3-d]pyrimidin-2-YL]-N-methylglycinamides.

The title compounds were synthesized by cyclizing 3-dimethylaminomethylene-4-chromanone with creatine to give the acid 2 that was successively converted into the corresponding amides 3a-f via diphenylphosphorylazide and the relevant amines. The free acid 2 and some of 3a-f showed antiinflammatory, hypotensive and antiarrhythmic properties.

2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles with antiarrhythmic and local anaesthetic activities.

The synthesis of novel 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles 4a-f, starting from N-phenyl-3,4-dihydro-1(2H)-oxonaphthalene-2-carbothioamide and the proper arylhydrazines, is described. Title compounds were evaluated for antiinflammatory, analgesic, antipyretic, antiarrhythmic, hypotensive, local anaesthetic and platelet antiaggregating activities; some of them showed an appreciable antiarrhythmic activity in rats and a good level of infiltration anaesthesia in mice.

5-[[omega-(Dialkylamino)alkoxy]methylene]-1,3,3-trimethyl-2- oxabicyclo [2.2.2.]octan-6-ones with hypotensive, local anesthetic, antiarrhythmic and other activities.

The synthesis of 5-[[omega-(dialkylamino)alkoxy]methylene]-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-6-ones by reaction of (+)-5-(hydroxymethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan- 6-one with a series of omega-(chloroalkyl)dialkylamines in the presence of potassium carbonate is described. Some compounds showed strong hypotensive, local anesthetic and antiarrhythmic activity in rats and mice, as well as moderate analgesic, antipyretic and in vitro platelet antiaggregating activity.

3,5-Diphenyl-1H-pyrazole derivatives. XII. N-substituted 4-amino-1-(2-hydroxy- or 2-alkylaminoethyl)-3,5-diphenyl-1H-pyrazoles with local anesthetic, analgesic and platelet antiaggregating activities.

The synthesis of 4-amino-3,5-diphenyl-1H-pyrazole-1-ethanol, as well as of their N-methyl, N-ethyl and N,N-dimethyl derivatives is described. A series of 1-(2-alkylaminoethyl)-3,5-diphenyl-1H-pyrazole-4-amines and of N-substituted 4-dimethylamino-3,5-diphenyl-1H-pyrazole-1-ethanamines were also prepared. Some of the above compounds showed remarkable local anesthetic, analgesic and in vitro platelet antiaggregating activities, as well as moderate antiinflammatory and antipyretic activities in rats and mice.