ABSTRACT
A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.
ABSTRACT
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Subject(s)
Azepines/chemistry , Central Nervous System Agents/chemistry , Pyrimidines/chemistry , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Animals , Azepines/chemical synthesis , Azepines/pharmacology , Blood-Brain Barrier/metabolism , CHO Cells , Central Nervous System Agents/chemical synthesis , Central Nervous System Agents/pharmacology , Cricetulus , Dogs , Drug Design , Humans , Madin Darby Canine Kidney Cells , Permeability , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacology , Structure-Activity Relationship , Urinary Incontinence, Stress/drug therapyABSTRACT
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
A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Methicillin Resistance , Staphylococcus aureus/drug effectsABSTRACT
The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]
