Tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists.

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Vu CB, Kiesman WF, Conlon PR, Lin KC, Tam M, Petter RC, Smits G, Lutterodt F, Jin X, Chen L, Zhang J

Tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists.

J Med Chem. 2006 Nov 30;49(24):7132-9.

PubMed ID

17125265 [ View in PubMed

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Abstract

Novel tricyclic imidazoline antagonists of the adenosine A1 receptor are described. For key compounds, the selectivity level over other adenosine receptor subtypes is examined along with their in vivo effects in a rat diuresis model. Compound 14, the (R)-isomer of 7,8-dihydro-8-ethyl-2-(4-bicyclo[2.2.2]octan-1-ol)-4-propyl-1H-imidazo[2,1-i]puri n-5(4H)-one, is a particularly potent adenosine A1 receptor antagonist with good selectivity over the other three adenosine receptor subtypes: A1 (human) Ki=22 nM; A2A (human) Ki=4400 nM; A2B (human) Ki=580 nM; A3 (human) Ki>or=10,000 nM. Imidazoline 14 is a competitive adenosine A1 receptor antagonist with a pA2 value of 8.88 and is highly soluble in water (>100 mg/mL). In addition, it has an oral bioavailability of 84% and an oral half-life of 3.8 h in rats. When orally administered in a rat diuresis model, compound 14 promoted sodium excretion (ED50=0.01 mg/kg). This level of efficacy is comparable to that of BG9928, a selective adenosine A1 receptor antagonist that is currently in clinical trials as a treatment for congestive heart failure. Additional modifications to 14 also showed that the bridgehead hydroxyl group could be replaced with a propionic acid (compound 36) without a significant loss in binding affinity or in vivo activity.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tonapofylline	Adenosine receptor A1	Protein	Humans	Unknown	Not Available	Details