RESUMEN
We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CHO , Permeabilidad Capilar/efectos de los fármacos , Chlorocebus aethiops , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Cristalografía por Rayos X , Entropía , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformación Molecular , Pleuresia/tratamiento farmacológico , Conejos , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/síntesis química , Analgésicos/síntesis química , Benzopiranos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Sulfonamidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Presión Sanguínea/efectos de los fármacos , Células CHO , Calcio/metabolismo , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Masculino , Microsomas/metabolismo , Dolor/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B1/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
One common synthetic route creates small-molecule libraries directed toward two functionally distinct target families. The novel structural template 1 can independently display the necessary pharmacophore patterns for inhibition of members of two different biomolecular target families, the matrix metalloproteinases (MMPs) or the phosphodiesterases (PDEs). The incorporation of multiple target family directed design elements into combinatorial library design could help expedite the pharmaceutical lead discovery process. Z=OR' (PDE4), H (MMPs).
RESUMEN
The present paper describes the development of a new series of P2Y12 receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 µM, aq solubility <0.1 µM, microsomal CLint (HLM) ≥300 µM/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 µM, aq solubility = 90 µM, microsomal CLint (HLM) = 70 µM/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 µM, aq solubility = 83 µM, microsomal CLint (HLM) = 28 µM/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality.
Asunto(s)
Ácidos Nicotínicos/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y12/metabolismo , Urea/análogos & derivados , Animales , Estructura Molecular , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/química , Antagonistas del Receptor Purinérgico P2Y/síntesis química , Antagonistas del Receptor Purinérgico P2Y/química , Ratas , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
BACKGROUND: Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis. RESULTS: Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole. CONCLUSION: The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.
Asunto(s)
Oxazoles/química , Oxazoles/farmacología , Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/farmacología , Animales , Humanos , Enlace de Hidrógeno , Microsomas/metabolismo , Modelos Moleculares , Oxazoles/metabolismo , Oxazoles/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Cholesteryl ester transfer protein is a plasma glycoprotein that transfers cholesterol ester between lipoprotein particles. Inhibition of this protein, in vitro and in vivo, produces an increase in plasma high density lipoprotein cholesterol (HDL-C). This communication will describe the SAR and synthesis of a series of substituted tetrahydroquinoxaline CETP inhibitors from early mu lead to advanced enantiomerically pure analogs.
Asunto(s)
Química Farmacéutica/métodos , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Ésteres/química , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Tetrazoles/química , Animales , HDL-Colesterol/metabolismo , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Conformación Molecular , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.