Thiazole and thiadiazole analogues as a novel class of adenosine receptor antagonists

Novel. classes of heterocyclic compounds as adenosine antagonists were deve loped based on a template approach. Structure-affinity relationships reveal ed insights for extended knowledge of the receptor-ligand interaction. We r eplaced the bicyclic heterocyclic ring system of earlier described isoquino line and quinazoline adenosine A(3) receptor ligands by several monocyclic rings and investigated the influence thereof on adenosine receptor affinity . The thiazole or thiadiazole derivatives seemed most promising, so we cont inued our investigations with these two classes of compounds. The large dif ference between a pyridine and isoquinoline ring in binding adenosine Al an d Ag receptors showed the importance of the second ring of the isoquinoline ligands. We prepared several N-[4-(2-pyridyl)thiazol-2-yl] benzamides, and these compounds showed adenosine affinities in the micromolar range. Most surprising in the series of the N-[4-(2-pyridyl)thiazol-2-yl]amides were th e retained adenosine affinities by introduction of a cylopentanamide instea d of the benzamide. A second series of compounds, the thiadiazolobenzamide series of compounds, revealed potent and selective adenosine receptor antag onists, especially N-(3-phenyl-1,2,4-thiadiazol-5-yl)-4-hydroxybenzamine (L UF5437, 8h) showing a Ki value of 7 nM at the adenosine Al receptor and N-( 3-phenyl-1,2, 4-thiadiazol-5-yl)-4methoxybenzamide (LUF5417, 8e) with a K-i value of 82 nM at the adenosine A(3) receptor. 4-Hydroxybenzamide 8h is th e most potent adenosine A(1) receptor antagonist of this new class of compo unds. Structure-affinity relationships showed the existence of a steric res triction at the para-position of the benzamide ring for binding adenosine A (1) and A(3) receptors. The electronic nature of the 4-substituents played an important role in binding the adenosine A(3) receptor. Cis- and trans-4- substituted cyclohexyl derivatives were made next to the 4-substituted benz amide analogues. We used them to study the proposed specific interaction be tween the adenosine Al receptor and the 4-hydroxy group of this class of th iadiazolo compounds, as well as a suggested special role for the 4-methoxy group in binding the A(3) receptor. Both the adenosine A(1) and A(3) recept or slightly preferred the trans-analogues over the cis-analogues, while all compounds showed low affinities at the adenosine A(2A) receptor. Our inves tigations provided the potent and highly selective adenosine A(1) antagonis t N-(3-phenyl-1,2,4-thiadiazol-5-yl)-trans-4-hydroxycyclohexanamide (VUF547 2, 8m) showing a K-i value of 20 nM. A third series of compounds was formed by urea analogues, N-substituted with thiazolo and thiadiazolo heterocycle s. The SAR of this class of compounds was not commensurate with the SAR of the previously described quinazoline urea. On the basis of these findings w e suggest the existence of a special interaction between adenosine receptor s and a region of high electron density positioned between the thia(dia)zol e ring and phenyl(pyridyl) ring. Molecular electrostatic potential contour plots showed that for this reason the ligands need either a thiadiazole rin g instead of a thiazole or a 2-pyridyl group instead of a phenyl. The deriv ed novel classes of antagonists will be useful for a better understanding o f the molecular recognition at the adenosine receptors.