ABSTRACT
To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as negative controls. A systematic analysis of these ligands identified a set of preferred parameters for physicochemical properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-[(18)F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [(18)F]PF-05270430 (5).
Subject(s)
Azabicyclo Compounds/chemical synthesis , Azetidines/chemical synthesis , Brain/diagnostic imaging , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Radiopharmaceuticals/chemical synthesis , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacokinetics , Azetidines/chemistry , Azetidines/pharmacokinetics , Brain/enzymology , Computer Simulation , Databases, Factual , Dogs , Drug Design , Fluorine Radioisotopes , Humans , Ligands , Macaca fascicularis , Male , Models, Biological , Permeability , Positron-Emission Tomography , Protein Binding , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The design and synthesis of novel opiates are reported. Based on the message-address principle a novel class of 4,4- and 3,3-biaryl piperidines was designed and synthesized. Biological evaluation confirmed that these compounds exhibit high affinity and selectivity for the delta opioid receptor. Key structure-activity relationships that influence affinity, selectivity, functional activity and clearance are reported.
Subject(s)
Ligands , Piperidines/chemistry , Receptors, Opioid, delta/antagonists & inhibitors , Animals , Drug Design , Humans , Microsomes, Liver/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacology , Protein Binding , Rats , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Structure-Activity RelationshipABSTRACT
Advances in the field of drug discovery have brought an explosion in the quantity of data available to medicinal chemists and other project team members. New strategies and systems are needed to help these scientists to efficiently gather, organize, analyze, annotate, and share data about potential new drug molecules of interest to their project teams. Herein we describe a suite of integrated services and end-user applications that facilitate these activities throughout the medicinal chemistry design cycle. The Automated Data Presentation (ADP) and Virtual Compound Profiler (VCP) processes automate the gathering, organization, and storage of real and virtual molecules, respectively, and associated data. The Project-Focused Activity and Knowledge Tracker (PFAKT) provides a unified data analysis and collaboration environment, enhancing decision-making, improving team communication, and increasing efficiency.
Subject(s)
Chemistry, Pharmaceutical/methods , Cooperative Behavior , Group Processes , Statistics as Topic/methods , Workflow , Chemistry, Pharmaceutical/organization & administration , Communication , Drug Design , Industry , Information Storage and Retrieval , Knowledge , User-Computer InterfaceABSTRACT
The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.
