RESUMO
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.
Assuntos
Benzopiranos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzopiranos/farmacologia , Carragenina/farmacologia , Química Farmacêutica/métodos , Dor Crônica/tratamento farmacológico , Desenho de Fármacos , Humanos , Hiperalgesia/tratamento farmacológico , Concentração Inibidora 50 , Cinética , Modelos Químicos , Coelhos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Benzopiranos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Cromanos/síntese química , Sulfonamidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Cromanos/farmacocinética , Cromanos/farmacologia , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Microssomos/metabolismo , Dor/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Receptor B1 da Bradicinina/agonistas , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Ftalazinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Ftalazinas/química , Ftalazinas/farmacologia , Coelhos , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antagonistas de Receptor B1 da Bradicinina , Tetra-Hidronaftalenos/química , Ácido Acético/química , Administração Oral , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Disponibilidade Biológica , Concentração Inibidora 50 , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg(-1) in fasted mice.