ABSTRACT
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthus Reaction/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Administration, Oral , Aniline Compounds/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Crystallography, X-Ray , Drug Discovery , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Syk KinaseABSTRACT
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
Subject(s)
Benzamides/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Glucocorticoid/agonists , Administration, Oral , Animals , Benzamides/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Prednisolone , Pyrazoles/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.
Subject(s)
Boronic Acids/chemistry , Quinolines/chemical synthesis , Catalysis , Palladium/chemistry , Quinolines/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding Sites , Cell Line , Drug Partial Agonism , Humans , Mammary Tumor Virus, Mouse/genetics , Models, Molecular , Molecular Mimicry , NF-kappa B/genetics , Receptors, Glucocorticoid/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Cytomegalovirus/enzymology , Lactams/chemical synthesis , Lactams/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Serine Endopeptidases/metabolism , Animals , Antiviral Agents/blood , Biological Availability , Brain/metabolism , Cells, Cultured , Dogs , Drug Design , Enzyme-Linked Immunosorbent Assay , Eye/metabolism , Ganciclovir/pharmacology , Guinea Pigs , Half-Life , Humans , Indicators and Reagents , Kinetics , Mass Spectrometry , Models, Molecular , Protease Inhibitors/blood , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Mechanism-based inhibitors of HCMV protease, which are stable to human plasma (> or = 20 h) and have single-figure potency in the microM range against HCMV protease, have been developed based on the dansylproline alpha-methyl pyrrolidine-5,5-trans-lactam nucleus.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytomegalovirus/enzymology , Lactams/pharmacology , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Dansyl Compounds/chemistry , Drug Stability , Half-Life , Humans , Inhibitory Concentration 50 , Lactams/blood , Lactams/chemistry , Proline/chemistry , Protease Inhibitors/blood , Pyrrolidines/blood , Spectrometry, Mass, Electrospray IonizationABSTRACT
The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.
Subject(s)
Benzofurans/chemical synthesis , Oxytocin/antagonists & inhibitors , Animals , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Drug Design , Female , Humans , Kinetics , Models, Molecular , Molecular Conformation , Rats , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.
