6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 adenosine receptor agonist allosteric enhancers having improved potency

J Med Chem. 2005 Aug 11;48(16):5131-9. doi: 10.1021/jm049132j.

Abstract

Allosteric enhancers (AEs) of the A(1) adenosine receptor (A(1)AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A(1)AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a-aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a-aj. Binding studies using membranes from cells stably expressing human A(1)ARs, A(2A)ARs, or A(3)ARs evaluated AE activity and receptor subtype selectivity. The EC(50) of the AE activities of compounds 3m-o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 muM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 microM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A(2A)AR and only minimal activity at the A(3)AR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine A1 Receptor Agonists*
  • Adenosine A1 Receptor Antagonists
  • Allosteric Regulation
  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Binding, Competitive
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Humans
  • Indenes / chemical synthesis*
  • Indenes / chemistry
  • Indenes / pharmacology
  • Radioligand Assay
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Amines
  • Indenes
  • Thiazoles