ABSTRACT
Heterocycle-fused azepines are discussed as potent 5-HT2C receptor agonists with excellent selectivity over 5-HT2B agonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4-d]azepines. By comparison with earlier published work, in vitro assays predict a high probability for achieving CNS penetration for a potent and selective compound 15a, a pre-requisite to achieve in vivo efficacy.
Subject(s)
Azepines/chemistry , Drug Design , Pyridazines/chemistry , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Azepines/chemical synthesis , Azepines/metabolism , Dogs , Humans , Madin Darby Canine Kidney Cells , Protein Binding , Receptor, Serotonin, 5-HT2B/chemistry , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Agonists/metabolism , Structure-Activity RelationshipABSTRACT
The first example of an inhibitor of the kinase TAK1 that binds in the DFG-out conformation is disclosed. These preliminary studies used kinase-targeted screening and structure-based drug design to create a molecule with dual pharmacological inhibition of p38 and TAK1 that demonstrated significant activity in a cell-based, anti-inflammatory assay.
Subject(s)
Anti-Inflammatory Agents/chemistry , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
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
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Subject(s)
Piperazines/chemical synthesis , Pyridazines/chemical synthesis , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Animals , Dogs , Drug Design , Humans , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Structure-Activity Relationship , Urinary Incontinence, Stress/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
An alkylidene carbene 1,5-CH insertion has been used as a key step in an enantioselective total syntheses of omuralide, its C7-epimer, and (+)-lactacystin. An additional noteworthy feature of the synthesis is the use of a novel oxidative deprotection procedure, utilizing DMDO, for the conversion of a late-stage benzylidene acetal into a primary alcohol and a secondary benzoate ester.
Subject(s)
Acetylcysteine/analogs & derivatives , Lactones/chemical synthesis , Acetylcysteine/chemical synthesis , Acetylcysteine/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Crystallography, X-Ray , Lactones/chemistry , StereoisomerismABSTRACT
[reaction: see text] The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally applicable. Additionally, it was found that oxidation of a benzofuran by NaIO(4) on silica produced a long-lived semiquinone radical.
Subject(s)
Quinones/chemistry , Quinones/chemical synthesis , Rifabutin/analogs & derivatives , Catalysis , Indicators and Reagents , Molecular Structure , Oxidation-Reduction , Rifabutin/chemical synthesis , Rifabutin/chemistry , StereoisomerismABSTRACT
The convergent synthesis of a benzofuran analog of the carbacyclic ansa compound kendomycin has been achieved by assembling three major fragments by means of epoxide opening and directed ortho lithiation. The crucial tetrahydropyran ring was formed by a highly stereoselective cationic cyclization. Analysis of all synthesized tetrahydropyran-arene compounds reveals a hindered sp(2)-sp(3) rotation, which results in rotational isomers or atropisomers affecting macrocyclization reactions. The latter could only be achieved by means of Horner-Wadsworth-Emmons olefination.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Rifabutin/chemical synthesis , Anti-Bacterial Agents/chemistry , Chemistry, Organic/methods , Models, Molecular , Molecular Structure , Rifabutin/analogs & derivatives , Rifabutin/chemistry , StereoisomerismABSTRACT
[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.
