ABSTRACT
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Subject(s)
Asthma/drug therapy , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Asthma/metabolism , Dose-Response Relationship, Drug , Drug Resistance/drug effects , Humans , Male , Mice , Mice, Inbred Strains , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pulmonary Disease, Chronic Obstructive/metabolism , Steroids/pharmacology , Structure-Activity Relationship , U937 CellsABSTRACT
Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
Subject(s)
Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Catalytic Domain , Cell Line , Computer Simulation , Humans , Indazoles/chemistry , NF-kappa B/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
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
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
Subject(s)
Glucocorticoids/agonists , Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Amides/chemistry , Binding Sites , Chemistry, Pharmaceutical/methods , Drug Design , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Stereoisomerism , Steroids/chemistryABSTRACT
A recently released report of the Exploring Accreditation Project affirmatively answered the questions regarding the desirability and feasibility of establishing a national voluntary public health accreditation program. The report's recommendations were made after 10 months of inquiry from public health experts, elected officials, the general public health workforce, academicians, and other interested parties, more than 650 public health professionals in all. Recommendations regarding how such a program might be implemented insofar as its governance, principles for standards development, financing and incentives, and evaluation were included. The report provides a blueprint for establishing a national voluntary public health accreditation program. This article describes key aspects of the Steering Committee recommendations, with limited linkage to implementation strategies where relevant, in the four areas in which the project was designed. Details are provided in the final reports of the Steering Committee (www.exploringaccreditation.org) and in other articles in this issue.
Subject(s)
Accreditation/standards , Public Health/standards , State Health Planning and Development Agencies/standards , Advisory Committees , Quality Assurance, Health Care , United StatesABSTRACT
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Lactams/chemistry , Lactams/pharmacology , Pyrrolidines/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Amino Acid Sequence , Carrier Proteins/metabolism , Drug Design , Hepacivirus/drug effects , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Lactams/chemical synthesis , Microbial Sensitivity Tests , Pyrrolidines/chemical synthesis , Stereoisomerism , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Viral Proteins/metabolismABSTRACT
Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.
