ABSTRACT
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
Subject(s)
Biphenyl Compounds/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridazines/pharmacology , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Male , Models, Molecular , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.
Subject(s)
Acetates/chemistry , Acetates/pharmacology , Piperidines/chemistry , Pyrazoles/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Half-Life , Humans , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.
Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Half-Life , Humans , Indoles/chemistry , Injections, Intravenous , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.
Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Half-Life , Humans , Hydrogen Bonding , Models, Chemical , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.
Subject(s)
Acetates/chemistry , Acetates/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Humans , Pyrazoles/chemical synthesis , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.
Subject(s)
Acetates/chemistry , Pyrazoles/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Half-Life , High-Throughput Screening Assays , Protein Binding , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.
Subject(s)
Drug Discovery , Receptors, Lysosphingolipid/agonists , Thiadiazoles/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Lymphopenia/blood , Models, Molecular , Molecular Structure , Rats , Sphingosine-1-Phosphate Receptors , Structure-Activity Relationship , Thiadiazoles/administration & dosage , Thiadiazoles/chemical synthesisABSTRACT
The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.
Subject(s)
Biphenyl Compounds/chemistry , Crotonates/chemistry , Enzyme Inhibitors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Toluidines/chemistry , Animals , Arthritis, Experimental/drug therapy , Binding Sites , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Computer Simulation , Dihydroorotate Dehydrogenase , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Humans , Hydroxybutyrates , Nitriles , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Protein Structure, Tertiary , Rats , Structure-Activity RelationshipABSTRACT
BACKGROUND: Most studies indicate that ABO incompatibility has no effect on the clinical outcome after allogeneic peripheral blood progenitor cell (PBPC) transplantation (allo-PBPCT). However, it carries additional risks of hemolytic reactions, delayed red blood cell (RBC) engraftment, and pure red cell aplasia (PRCA). Data on these events after reduced intensity conditioning (RIC) regimens are limited, but recent studies have suggested a higher transplant-related mortality (TRM) and morbidity in this setting. STUDY DESIGN AND METHODS: We investigated the impact of ABO-matching on the outcome of 77 patients included in a prospective RIC allo-PBPCT protocol, focusing on engraftment, transfusion requirements, graft-versus-host disease, TRM, and survival. RESULTS: There were 17 (22%) minor and 8 (10%) major ABO-incompatible transplants. No graft failures were observed. After major ABO-incompatible grafts, RBC engraftment was delayed, longer thrombocytopenia periods were documented, and transfusion requirements increased. A transient mild hemolysis occurred in 10 patients, 7 (41%) minor and 3 (37%) major ABO-mismatched. A PRCA was observed in a O+ patient with a pretransplant anti-Jka, grafted from an A + Jka+ donor. Graft-versus-host disease, disease progression, and TRM were not affected by ABO matching. CONCLUSION: ABO incompatibility was not associated with clinically relevant hemolysis after the RIC protocol used and did not impair the clinical outcome. PRCA was only observed in one patient, with a non-ABO RBC allo-antibody.
