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 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
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.
