title: 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.affiliation: Department of Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: William F
authors.initials: WF
authors.lastname: Kiesman
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Conlon
authors.forename: Ko-Chung
authors.initials: KC
authors.lastname: Lin
authors.forename: Melissa
authors.initials: M
authors.lastname: Tam
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
authors.forename: Glenn
authors.initials: G
authors.lastname: Smits
authors.forename: Frank
authors.initials: F
authors.lastname: Lutterodt
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jin
authors.forename: Liqing
authors.initials: L
authors.lastname: Chen
authors.forename: Jianbo
authors.initials: J
authors.lastname: Zhang
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006207:Half-Life; D006325:Heart Atria / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D009318:Natriuresis / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C517059:7,8-dihydro-8-ethyl-2-(4-bicyclo(2.2.2)octan-1-ol)-4-propyl-1H-imidazo(2,1-i)purin-5(4H)-one; D058916:Adenosine A1 Receptor Antagonists; D001643:Bridged Bicyclo Compounds; D006575:Heterocyclic Compounds, 3-Ring; D048288:Imidazolines; D011687:Purines; D043683:Receptors, Adenosine A2