6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 adenosine receptor agonist allosteric enhancers having improved potency.
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.
Chordia
Mahendra D
MD
Department of Chemistry, University of Virginia, Charlottesville, VA 22901, USA.
Zigler
Molly
M
Murphree
Lauren J
LJ
Figler
Heidi
H
Macdonald
Timothy L
TL
Olsson
Ray A
RA
Linden
Joel
J
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000494:Allosteric Regulation; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000588:Amines; D007192:Indenes; D013844:Thiazoles