ABSTRACT
In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.
Subject(s)
Communicable Disease Control , Communicable Diseases/drug therapy , Congresses as Topic , Combined Modality Therapy , Communicable Diseases/epidemiology , Drug Discovery , Drug Evaluation, Preclinical , HIV Infections/drug therapy , Humans , Poverty , United KingdomABSTRACT
The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.
Subject(s)
Drug Delivery Systems/methods , Drug Discovery/methods , Drug Industry/methods , Drugs, Investigational , Animals , Drug Delivery Systems/statistics & numerical data , Drug Delivery Systems/trends , Drug Discovery/statistics & numerical data , Drug Discovery/trends , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/statistics & numerical data , Drug Evaluation, Preclinical/trends , Drug Industry/statistics & numerical data , Drug Industry/trends , Drugs, Investigational/administration & dosage , Humans , Statistics as Topic/methods , Statistics as Topic/trendsABSTRACT
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Subject(s)
Drug Design , Drug Evaluation, Preclinical/methods , Drug Industry/methods , Models, Statistical , Toxicity Tests/methods , Animals , Discriminant Analysis , Humans , Molecular Structure , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolismABSTRACT
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Subject(s)
Enzyme Inhibitors/chemistry , Isoxazoles/chemistry , Nitric Oxide Synthase Type II/antagonists & inhibitors , Pyridines/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mice , Microsomes, Liver/metabolism , Nitric Oxide Synthase Type II/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , RatsABSTRACT
Rising expenditure in pharmaceutical R&D has not been matched by increased productivity. There is an urgent need to solve the current high levels of pipeline attrition. Changing the current failed model of drug discovery and development, in which high numbers of candidate drugs are produced and high attrition is accepted, is essential. A different model is needed, in which the focus shifts to identifying better-quality candidate drugs that allow scientifically robust testing of disease and targets in humans. Lowering the risks of compound-based attrition in small-molecule drug discovery and development (ie, addressing toxicity, specificity, potency, duration and exposure) is achievable by improved control of physical properties and by setting more demanding candidate criteria. Separating the key scientific experiment--proof-of-concept clinical trials in humans--from commercial development imperatives is a necessary step for the industry.
Subject(s)
Drug Discovery/methods , Drug Industry , Animals , Drug Discovery/economics , Drug Evaluation, Preclinical/economics , Drug Evaluation, Preclinical/methods , Drug Industry/economics , Drug Industry/methods , Efficiency, Organizational , Humans , Models, Organizational , Pharmacokinetics , Research DesignABSTRACT
The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed. The aim is to identify the trends in physiochemical properties that favor a drug's successful passage through clinical development and on to the market. Two libraries were created, one of current development oral drugs and one of marketed oral drugs. Statistical analysis of the two showed that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean molecular weight of marketed oral drugs. It is also clear that the most lipophilic compounds are being discontinued from development.