ABSTRACT
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Subject(s)
Acetamides/therapeutic use , Bradykinin B1 Receptor Antagonists , Inflammation/drug therapy , Pain/drug therapy , Piperazines/therapeutic use , Acetamides/chemical synthesis , Acetamides/chemistry , Animals , Dogs , Inhibitory Concentration 50 , Mice , Models, Animal , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Rabbits , Rats , Receptor, Bradykinin B1/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
Subject(s)
Benzylamines/chemistry , Bradykinin B1 Receptor Antagonists , Sulfonamides/chemistry , Tetrahydronaphthalenes/chemistry , Administration, Oral , Animals , Pain/drug therapy , Rats , Receptor, Bradykinin B1/metabolism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Subject(s)
Bradykinin B1 Receptor Antagonists , Pain/drug therapy , Sulfones/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bradykinin B2 Receptor Antagonists , Chronic Disease , Humans , Rabbits , Rats , Rats, Sprague-Dawley , Sulfones/administration & dosageABSTRACT
Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.
Subject(s)
Acetamides/chemical synthesis , Bradykinin B1 Receptor Antagonists , Chemistry, Pharmaceutical/methods , Quinoxalines/chemical synthesis , Receptor, Bradykinin B1/chemistry , Acetamides/chemistry , Acetic Acid/chemistry , Amines , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Molecular Conformation , Molecular Structure , Protein Binding , Quinoxalines/pharmacology , Structure-Activity RelationshipABSTRACT
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
Subject(s)
Amides/chemical synthesis , Analgesics/chemical synthesis , Benzopyrans/chemical synthesis , Bradykinin B1 Receptor Antagonists , Chromans/chemical synthesis , Sulfonamides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Benzopyrans/pharmacokinetics , Benzopyrans/pharmacology , Blood Pressure/drug effects , CHO Cells , Calcium/metabolism , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Cricetulus , Humans , In Vitro Techniques , Inflammation/drug therapy , Male , Microsomes/metabolism , Pain/drug therapy , Rabbits , Rats , Rats, Sprague-Dawley , Receptor, Bradykinin B1/agonists , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.
