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

Article abstract of DOI:10.1021/jm049132j

Allosteric enhancers (AEs) of the A₁ adenosine receptor (A ₁AR) 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 A₁AR. 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 ₁ARs, A_2AARs, or A₃ARs evaluated AE activity and receptor subtype selectivity. The EC₅₀ of the AE activities of compounds 3m-o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A_2AAR and only minimal activity at the A₃AR. 2005 American Chemical Society.