ABSTRACT
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Subject(s)
Erectile Dysfunction/drug therapy , Phosphodiesterase I/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Purines/chemical synthesis , Purines/therapeutic use , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5 , Humans , Male , Models, Molecular , Molecular Structure , Piperazines/pharmacology , Purines/chemistry , Rats , Sildenafil Citrate , Structure-Activity Relationship , Sulfones , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic useABSTRACT
BACKGROUND: Combination therapy (risperidone and a mood stabilizer) for patients with a history of bipolar disorder (DSM-IV) and hospitalized for treatment of a manic episode was assessed in a 13-week study. METHOD: Subjects received flexible doses of a mood stabilizer (lithium or divalproex) plus placebo, risperidone, or haloperidol in a 3-week double-blind study. They could then enter a 10-week open-label study during which they received risperidone combined with a mood stabilizer. RESULTS: Of the 156 patients enrolled in the 3-week study, 85 entered the 10-week open-label extension, of whom 48 completed 10 weeks of treatment. The mean +/- SE doses of risperidone were 3.8 +/- 0.3 mg/day during the 3-week study and 3.1 +/- 0.2 mg/day during the 10-week study. At double-blind endpoint, mean reductions in Young Mania Rating Scale (YMRS) scores were significantly greater in patients receiving risperidone plus mood stabilizer than in those receiving placebo plus mood stabilizer (-14.3 vs. -8.2, p <.001). Further significant (p <.001) reductions were seen during the 10 weeks of treatment with risperidone plus mood stabilizer. Symptom remission (YMRS score Subject(s)
Anticonvulsants/therapeutic use
, Antipsychotic Agents/therapeutic use
, Bipolar Disorder/drug therapy
, Lithium/therapeutic use
, Adult
, Bipolar Disorder/diagnosis
, Bipolar Disorder/psychology
, Brief Psychiatric Rating Scale
, Double-Blind Method
, Drug Administration Schedule
, Drug Therapy, Combination
, Female
, Hospitalization
, Humans
, Male
, Psychiatric Status Rating Scales
, Severity of Illness Index
, Treatment Outcome
, Valproic Acid/therapeutic use
ABSTRACT
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Drug Delivery Systems/methods , Erectile Dysfunction/drug therapy , Erectile Dysfunction/enzymology , Guanine/chemistry , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/administration & dosage , Humans , Male , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , Polycyclic Compounds/administration & dosage , Polycyclic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
