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  • Synthesis pharmacological evaluation for the binding at hA h

    2023-01-30

    Synthesis, pharmacological evaluation for the binding at hA, hA and hA ARs, and efficacy at hA subtype of the synthesized compounds, together with the assessment of their theoretical ADME properties were the guidelines in this preliminary drug discovery investigation. The synthetic pathways which yielded compounds – and the relative intermediates are illustrated in , . Litigation of commercially available thiophene-3-carboxylic azilsartan medoxomil synthesis followed by (hetero)arylaldehyde addition provided the suitable substituted 2-hydroxymethylthiophene-3-carboxylic acid which was not isolated (). Oxidation of the alcohol function with KMnO generated the ketoacids –, , which were reacted with hydrazine hydrate in ethanol at reflux to yield the 7-substituted[2,3-]pyridazin-4(5H)-ones –., , The final targets – were synthesized following two different procedures as follows. The 5-alkyl substituted derivatives – and the corresponding 5-N-amino-compounds – were obtained by reacting –, , with NaH followed by addition respectively of the opportune alkylbromide or hydroxylamine-O-sulfonic acid in DMF at room temperature. Both the 5,7-diethylthieno[2,3-]pyridazin-4(5H)-one and 5,7-diethyl-2-phenylthieno[2,3-]pyridazin-4(5H)-one were obtained following the procedure reported in . By reacting thiophene-3-carboxylic acid with LDA in anhydrous tetrahydrofuran followed by addition of commercially available -methoxy--methylpropanamide afforded the desired ketoacid intermediate . The latter was cyclized with hydrazine hydrate to yield the pyridazinone which was alkylated at 5-position with ethylbromide to give compound . Selective bromination of the thienopyridazinone moiety of at position 2 with bromine in aqueous acid acetic solution at 70 °C produced the corresponding 2-bromo derivative which was reacted with phenylboronic acid in alkaline medium in the presence of tetrakis to afford the final compound . All the reported compounds – were tested for their ability to displace specific [H]DPCPX ([H]-8-cyclopentyl-1,3-dipropylxanthine), [H]ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-][1,3,5]triazin-5-ylamino]ethyl)phenol) and [I]AB-MECA ([I]--(4-aminobenzyl)--methylcarboxamidoadenosine) binding from hA hA and hA receptors, respectively. Potency of the compounds at the hA subtype was investigated by measuring their inhibitory effect on 200 nM NECA (5′--ethylcarboxamidoadenosine)-stimulated cAMP levels in Chinese Hamster Ovary (CHO) cells transfected with the hA receptor. The affinity data (expressed as K) reported in indicate that we have produced some new AR ligands endowed with modest affinity for the hA subtype. None of the herein reported compounds – shows any activity at the hAAR since, in the cAMP experiments, the percentage of inhibition (I%) of each is equal only to 1%. To a lesser extent, this can also be applied to the results obtained in hA and hA AR binding experiments even though some compounds (, , , and ) exhibit K values in the high micromolar range. Affinity values in this range have also been found for the A subtype, compounds , – and showing 1153 < K (µM) < 3721. In contrast, compounds – present the highest affinity for the hAAR, the K values ranging from 912 to 113 nM. Despite the low or moderate affinity of the majority of the reported derivatives these data are encouraging and suggest that the thieno[3,2-]pyridazin-5(4H)-one ring system can be considered as a new scaffold for the development of new AR ligands. Starting from the 7-phenyl-substituted derivative , better results were obtained when 7-position was functionalized with a heteroaromatic substituent (see compounds – for comparison) that exerts the maximum profitable effect for the binding at AAR when it is a thiazol-2-yl moiety (derivative ). Other than position 7 of the thienopyridazinone scaffold, also R substituent was modified by replacement of the ethyl group of with the more hindering isopropyl substituent leading to derivative that maintains the hAAR affinity in the same range. No influence was observed on the other ARs. In contrast, introduction at position 5 of a primary amino group produced a reduction of the hA binding affinity (compounds –).