ABSTRACT
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
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Esters/chemistry , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Tetrazoles/chemistry , Animals , Cholesterol, HDL/metabolism , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Molecular Conformation , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Bradykinin B1 Receptor Antagonists , Chromans/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , CHO Cells , Capillary Permeability/drug effects , Chlorocebus aethiops , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Cricetulus , Crystallography, X-Ray , Entropy , Humans , In Vitro Techniques , Models, Molecular , Molecular Conformation , Pleurisy/drug therapy , Rabbits , Rats , Species Specificity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Bradykinin B1 Receptor Antagonists , Tetrahydronaphthalenes/chemistry , Acetic Acid/chemistry , Administration, Oral , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , Inhibitory Concentration 50 , Piperidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The addition of simple pentadienyltosylamide derivatives to the two-carbon electrophile phenyl(propynyl)iodonium triflate initiates a sequence of transformations that furnishes complex, highly functionalized cyclopentenannelated dihydropyrrole products in moderate yields with complete stereoselection. This sequence demonstrates that diyls resulting from homolytic scission of alkylidene carbene-alkene adducts can be readily accessed under mild experimental conditions and that, in the presence of appropriate pendant functionality, these diyls can productively cyclize. The isomeric isoprene-derived tosylamides follow an abbreviated reaction course and deliver azabicyclo[3.1.0]hexanes via an isomerization that competes with diyl formation.
