2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure-Activity Relationships of Potent Adenosine Receptor Antagonists.

2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A3 AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Ki human A3 AR 1.16 nm) and 5'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, Ki human A3 AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1 /A3 antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, Ki human A1 AR 51.6 nm, human A3 AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, Ki human A1 AR 131 nm, A2A AR 32.7 nm, A2B AR 150 nm, A3 AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, Ki human A1 AR 67.7 nm, A2A AR 13.6 nm, A2B AR 75.0 nm, A3 AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.

Synthesis and Bronchodilator Studies of Some Novel 6-Alkyl/Aryl-1,2,4-Triazino[4,3-c]Quinazolines.

A series of alkyl- and aryl-1,2,4-triazino[4,3-c]quinazolines (5a-h and 8a-h) were synthesized and characterized. The title compounds were evaluated for their in vivo bronchodilator activity on guinea pigs. All the test compounds exhibited good protection against histamine-induced bronchospasm. The structure-activity relationships based on the results obtained for these series were studied. Incorporation of an aryl ring with halo substitution to the theophylline bioisostere increases its potency. Among the compounds tested, 5b was found to be the most potent with 88.7% protection against histamine-induced bronchospasm compared to the standard compound aminophylline (87.8%).