title: 2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure-Activity Relationships of Potent Adenosine Receptor Antagonists.
abstract: 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 A3AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Kihuman A3AR 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, Kihuman A3AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1/A3antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, Kihuman A1AR 51.6 nm, human A3AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, Kihuman A1AR 131 nm, A2AAR 32.7 nm, A2BAR 150 nm, A3AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, Kihuman A1AR 67.7 nm, A2AAR 13.6 nm, A2BAR 75.0 nm, A3AR 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.
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Burbiel
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Wadih
authors.initials: W
authors.lastname: Ghattas
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Küppers
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Meryem
authors.initials: M
authors.lastname: Köse
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Lacher
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Herzner
authors.affiliation: University College of Pharmaceutical Sciences, Kakatiya University, 506 009, Warangal, India.
authors.forename: Rajan Subramanian
authors.initials: RS
authors.lastname: Kombu
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.|University College of Pharmaceutical Sciences, Kakatiya University, 506 009, Warangal, India.
authors.forename: Raghuram Rao
authors.initials: RR
authors.lastname: Akkinepally
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hockemeyer
authors.affiliation: Pharmazeutische Chemie I, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, An der Immenburg 4, 53121, Bonn, Germany. christa.mueller@uni-bonn.de.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D018047:Receptors, Purinergic P1; D014230:Triazoles
keywords: A3 adenosine receptor; antagonists; iminoquinazolinamines; microwave-assisted synthesis; species differences