ABSTRACT
Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
Subject(s)
Acids/chemical synthesis , Alanine/chemical synthesis , Neprilysin/antagonists & inhibitors , Oxazoles/chemistry , Oxazoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Acids/chemistry , Acids/pharmacology , Alanine/chemistry , Alanine/pharmacology , Crystallography, X-Ray , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistryABSTRACT
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 5/chemistry , Phosphodiesterase 5 Inhibitors , Pyrazines/chemical synthesis , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Catalytic Domain , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 6/chemistry , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Protein Structure, Tertiary , Pyrazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Subject(s)
4-Aminopyridine/analogs & derivatives , Chemistry, Pharmaceutical/methods , Ether-A-Go-Go Potassium Channels/chemistry , Receptors, Opioid, delta/agonists , 4-Aminopyridine/chemical synthesis , 4-Aminopyridine/pharmacology , Analgesics, Opioid/pharmacology , Animals , Cell Line , Combinatorial Chemistry Techniques , Drug Design , ERG1 Potassium Channel , Electromyography/methods , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Models, Chemical , Rats , Receptors, Opioid, delta/chemistry , Structure-Activity RelationshipABSTRACT
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.
Subject(s)
Amino Acids/chemical synthesis , Fibrinolysis/drug effects , Fibrinolytic Agents/chemical synthesis , Imidazoles/chemical synthesis , Thrombin/metabolism , Amino Acids/pharmacokinetics , Amino Acids/pharmacology , Animals , Binding Sites , Biological Availability , Blood Loss, Surgical/prevention & control , Carboxypeptidase B/chemistry , Catalytic Domain , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Half-Life , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Models, Molecular , Molecular Structure , Pancreas/enzymology , Rabbits , Stereoisomerism , Structure-Activity Relationship , Swine , Venous Thromboembolism/drug therapyABSTRACT
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
