ABSTRACT
Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.
Subject(s)
Adenosine A2 Receptor Antagonists , Pulmonary Disease, Chronic Obstructive/drug therapy , Xanthines/chemical synthesis , Xanthines/pharmacology , Animals , Binding Sites , Cell Line , Cyclic AMP/analysis , Dose-Response Relationship, Drug , Drug Design , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Rats , Stereoisomerism , Structure-Activity Relationship , Xanthines/chemistryABSTRACT
A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
Subject(s)
Adenosine A2 Receptor Antagonists , Pyrazoles/pharmacology , Xanthines/pharmacology , Binding Sites , Drug Evaluation, Preclinical , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Xanthines/chemical synthesis , Xanthines/chemistryABSTRACT
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50=380 nM rat mitochondria) with favorable PK properties (F=93%, t(1/2)=13.6h, dog).
Subject(s)
Antioxidants/pharmacology , Antioxidants/pharmacokinetics , Fatty Acids/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/pharmacokinetics , Palmitoyl Coenzyme A/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Dogs , Fatty Acids/chemistry , Humans , Molecular Conformation , Oxidation-Reduction/drug effects , Palmitoyl Coenzyme A/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.
Subject(s)
Adenosine A1 Receptor Agonists , Anti-Arrhythmia Agents/chemical synthesis , Ethers/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Sulfides/chemical synthesis , Adenosine/metabolism , Animals , Anti-Arrhythmia Agents/pharmacokinetics , Arrhythmias, Cardiac/drug therapy , Atrioventricular Node/drug effects , Atrioventricular Node/metabolism , Binding Sites , Bundle of His/drug effects , Dose-Response Relationship, Drug , Ethers/pharmacokinetics , Guinea Pigs , Heart Rate/drug effects , Heart Rate/physiology , Receptor, Adenosine A1/metabolism , Structure-Activity Relationship , Sulfides/pharmacokineticsABSTRACT
New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat.
