ABSTRACT
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
Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.
Subject(s)
Computer-Aided Design , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Adenosine Monophosphate/metabolism , Allosteric Site , Glycogen Phosphorylase/chemistry , Glycogen Phosphorylase/metabolism , Glycogen Phosphorylase, Liver Form/antagonists & inhibitors , Glycogen Phosphorylase, Liver Form/chemistry , Glycogen Phosphorylase, Liver Form/metabolism , Glycogen Phosphorylase, Muscle Form/antagonists & inhibitors , Glycogen Phosphorylase, Muscle Form/chemistry , Glycogen Phosphorylase, Muscle Form/metabolism , Humans , In Vitro Techniques , Lead/chemistry , Lead/pharmacology , Models, Chemical , Molecular Structure , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , ThermodynamicsABSTRACT
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Acetates/chemistry , Acetates/pharmacokinetics , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Biological Availability , Dogs , HeLa Cells , Humans , Macaca mulatta , Molecular Structure , Monocytes/drug effects , Piperidines/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Naphthols/chemical synthesis , Adenosine Triphosphate/metabolism , Amino Acid Sequence , Animals , Binding Sites , Glycogen Phosphorylase/chemistry , Kinetics , Liver/enzymology , Mice , Models, Molecular , Molecular Conformation , Naphthols/pharmacology , Protein Conformation , Rats , Structure-Activity RelationshipABSTRACT
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Subject(s)
CCR5 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , CHO Cells , Chemokine CCL4 , Cricetinae , Half-Life , HeLa Cells , Humans , Hydrogen Bonding , Macrophage Inflammatory Proteins/metabolism , Piperidines/pharmacokinetics , Pyrrolidines/pharmacokinetics , RatsABSTRACT
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Pyrrolidines/pharmacokinetics , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Dogs , Half-Life , Humans , Leukocytes, Mononuclear , Macaca mulatta , Metabolic Clearance Rate , Piperidines/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.
Subject(s)
Apoptosis/drug effects , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Cytotoxicity, Immunologic/drug effects , Drug Design , Granzymes , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.
