ABSTRACT
Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose-response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489-98. ©2017 AACR.
Subject(s)
Antineoplastic Agents/therapeutic use , Dose-Response Relationship, Drug , Medical Oncology/trends , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Humans , United States , United States Food and Drug AdministrationSubject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/biosynthesis , Peptide Fragments/biosynthesis , Pyrazoles/pharmacology , Sulfonamides/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Celecoxib , Cyclooxygenase 2/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Peptide Fragments/cerebrospinal fluid , Pyrazoles/blood , Pyrazoles/therapeutic use , Sulfonamides/blood , Sulfonamides/therapeutic useABSTRACT
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.
Subject(s)
Amines/chemistry , Enzyme Inhibitors/chemistry , Nerve Tissue Proteins/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Pyridines/chemistry , Amines/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Neural Inhibition/drug effects , Nitric Oxide Synthase Type I , Pyridines/pharmacologyABSTRACT
Cholinesterase inhibitors vary in their selectivity for acetylcholinesterase versus butyrylcholinesterase. We examined several cholinesterase inhibitors and assessed the relative role of acetylcholinesterase versus butyrylcholinesterase inhibition in central and peripheral responses to these medications. Donepezil and icopezil are highly selective for acetylcholinesterase, whereas tacrine and heptylphysostigmine demonstrated greater potency for butyrylcholinesterase over acetylcholinesterase. All four compounds increased acetylcholine levels in mouse brains. Dose-response curves for tremor (central effect) and salivation (peripheral effect) showed that donepezil and icopezil possess a more favourable therapeutic index than the nonselective inhibitors, tacrine and heptylphysostigmine. Co-administration of the selective butyrylcholinesterase inhibitor tetraisopropylpyrophosphoramide (iso-OMPA) potentiated peripheral, but not central, effects of the selective acetylcholinesterase inhibitor icopezil. The improved therapeutic index observed in mice with icopezil is due to a high degree of selectivity for acetylcholinesterase versus butyrylcholinesterase, suggesting that high selectivity for acetylcholinesterase may contribute to the clinically favourable tolerability profile of agents such as donepezil in Alzheimer's disease patients.
