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

ChemMedChem. 2016 Oct 19;11(20):2272-2286. doi: 10.1002/cmdc.201600255. Epub 2016 Aug 17.

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 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.

Keywords: A3 adenosine receptor; antagonists; iminoquinazolinamines; microwave-assisted synthesis; species differences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Molecular Structure
  • Purinergic P1 Receptor Antagonists / chemical synthesis*
  • Purinergic P1 Receptor Antagonists / chemistry
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Rats
  • Receptors, Purinergic P1 / metabolism*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Heterocyclic Compounds
  • Purinergic P1 Receptor Antagonists
  • Quinazolines
  • Receptors, Purinergic P1
  • Triazoles