ABSTRACT
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Subject(s)
Azepines/chemical synthesis , Pyrimidines/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Animals , Azepines/chemistry , Azepines/pharmacology , Azepines/therapeutic use , Disease Models, Animal , Dogs , Male , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Rats , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Agonists/therapeutic use , Urinary Incontinence/drug therapyABSTRACT
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Subject(s)
Pyrimidinones/chemistry , Pyrimidinones/therapeutic use , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Humans , Pyrimidinones/pharmacology , Receptor, Serotonin, 5-HT2B/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Urethra/drug effects , Urinary Incontinence/drug therapyABSTRACT
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
Subject(s)
Dopamine Agonists/administration & dosage , Dopamine Agonists/chemical synthesis , Drug Design , Receptors, Dopamine D3/agonists , Administration, Intranasal , Animals , Crystallography, X-Ray , Dogs , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacokinetics , Humans , Models, Molecular , Molecular Structure , Rats , Receptors, Dopamine D3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.
