ABSTRACT
A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain.
Subject(s)
Benzopyrans/chemical synthesis , Bradykinin B1 Receptor Antagonists , Animals , Benzopyrans/pharmacology , Carrageenan/pharmacology , Chemistry, Pharmaceutical/methods , Chronic Pain/drug therapy , Drug Design , Humans , Hyperalgesia/drug therapy , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Rabbits , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.
Subject(s)
Bradykinin B1 Receptor Antagonists , Phthalazines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Dogs , Humans , Phthalazines/chemistry , Phthalazines/pharmacology , Rabbits , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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
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
Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors.
