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

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]purin-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.

• Authors: Chi B Vu, William F Kiesman, Patrick R Conlon, Ko-Chung Lin, Melissa Tam, Russell C Petter, Glenn Smits, Frank Lutterodt, Xiaowei Jin, Liqing Chen, Jianbo Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 24 Pg. 7132-9 (Nov 30 2006) ISSN: 0022-2623 [Print] United States
• PMID: 17125265 (Publication Type: Journal Article)

Chemical References

• 7,8-dihydro-8-ethyl-2-(4-bicyclo(2.2.2)octan-1-ol)-4-propyl-1H-imidazo(2,1-i)purin-5(4H)-one
• Adenosine A1 Receptor Antagonists
• Bridged Bicyclo Compounds
• Heterocyclic Compounds, 3-Ring
• Imidazolines
• Purines
• Receptors, Adenosine A2

Topics

• Adenosine A1 Receptor Antagonists
• Administration, Oral
• Animals
• Biological Availability
• Bridged Bicyclo Compounds (chemical synthesis, pharmacokinetics, pharmacology)
• Cerebral Cortex (metabolism)
• Corpus Striatum (metabolism)
• Half-Life
• Heart Atria (drug effects)
• Heterocyclic Compounds, 3-Ring (chemical synthesis, pharmacokinetics, pharmacology)
• Humans
• Imidazolines (chemical synthesis, pharmacokinetics, pharmacology)
• In Vitro Techniques
• Natriuresis (drug effects)
• Purines (chemical synthesis, pharmacokinetics, pharmacology)
• Radioligand Assay
• Rats
• Receptors, Adenosine A2 (metabolism)
• Solubility
• Stereoisomerism
• Structure-Activity Relationship