6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines:  A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency

• Published in: Journal of medicinal chemistry Vol. 48; no. 16; pp. 5131 - 5139
• Main Authors: Chordia, Mahendra D, Zigler, Molly, Murphree, Lauren J, Figler, Heidi, Macdonald, Timothy L, Olsson, Ray A, Linden, Joel
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 11.08.2005
• Subjects: Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Allosteric Regulation; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; Cell Line; Cricetinae; Cricetulus; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Radioligand Assay; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Human; Sulfur nitrogen heterocycle; Agonist; Rat; Rodentia; Benzene derivatives; A1 Adenosine receptor; Selectivity; Tricyclic compound; In vitro; Vertebrata; Mammalia; Structure activity relation; Allosteric regulation; Animal; Affinity; Aromatic compound; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049132j

Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) 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 A1ARs, A2AARs, 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 A2AAR and only minimal activity at the A3AR.