The influence of the 'organizational factor' on compound quality in drug discovery

Physicochemical properties such as lipophilicity and molecular mass are known to have an important influence on the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of small-molecule drug candidates. To assess the use of this knowledge in reducing the likelihood of compound-related attrition, the molecular properties of compounds acting at specific drug targets described in patents from leading pharmaceutical companies during the 2000–2010 period were analysed. Over the past decade, there has been little overall change in properties that influence ADMET outcomes, but there are marked differences in molecular properties between organizations, which are maintained when the targets pursued are taken into account. The target-unbiased molecular property differences, which are attributable to divergent corporate drug design strategies, are comparable to the differences between the major drug target classes. On the basis of our analysis, we conclude that a substantial sector of the pharmaceutical industry has not modified its drug design practices and is still producing compounds with suboptimal physicochemical profiles.

[1]  F. Pammolli,et al.  The productivity crisis in pharmaceutical R&D , 2011, Nature Reviews Drug Discovery.

[2]  Niklas Blomberg,et al.  Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules. , 2011, Bioorganic & medicinal chemistry letters.

[3]  J. Arrowsmith.  Trial watch: Phase II failures: 2008–2010 , 2011, Nature Reviews Drug Discovery.

[4]  R Scott Obach,et al.  Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination. , 2010, Journal of medicinal chemistry.

[5]  Nigel Greene,et al.  Physicochemical drug properties associated with in vivo toxicological outcomes: a review , 2009, Expert opinion on drug metabolism & toxicology.

[6]  M. Bunnage.  Getting pharmaceutical R&D back on target. , 2011, Nature chemical biology.

[7]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[8]  J. Peters,et al.  Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds , 2009, ChemMedChem.

[9]  S. Macdonald,et al.  Factors Determining the Selection of Organic Reactions by Medicinal Chemists and the Use of These Reactions in Arrays (Small Focused Libraries) , 2011 .

[10]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[11]  Marta Bellini,et al.  Straightforward recursive partitioning model for discarding insoluble compounds in the drug discovery process. , 2008, Journal of medicinal chemistry.

[12]  Michael J. Keiser,et al.  The Chemical Basis of Pharmacology , 2010, Biochemistry.

[13]  O. Hucke,et al.  Development of Specific “Drug‐Like Property” Rules for Carboxylate‐Containing Oral Drug Candidates , 2010, ChemMedChem.

[14]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[15]  Garry Pairaudeau,et al.  Creativity, innovation and lean sigma: a controversial combination? , 2011, Drug discovery today.

[16]  S. Teague,et al.  Learning lessons from drugs that have recently entered the market. , 2011, Drug discovery today.

[17]  Ian D. Wilson,et al.  Managing the challenge of chemically reactive metabolites in drug development , 2011, Nature Reviews Drug Discovery.

[18]  Stephen D Pickett,et al.  The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. , 2011, Drug discovery today.

[19]  S. Weinberg,et al.  Where We Are Now , 1973, Science.

[20]  M. Varma,et al.  Targeting intestinal transporters for optimizing oral drug absorption. , 2010, Current drug metabolism.

[21]  S. Bembenek,et al.  Ligand binding efficiency: trends, physical basis, and implications. , 2008, Journal of medicinal chemistry.

[22]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[23]  D. Bojanic,et al.  Impact of high-throughput screening in biomedical research , 2011, Nature Reviews Drug Discovery.

[24]  Sarma A R P Jagarlapudi,et al.  Database systems for knowledge-based discovery. , 2009, Methods in molecular biology.

[25]  P. Leeson,et al.  A comparison of physiochemical property profiles of development and marketed oral drugs. , 2003, Journal of medicinal chemistry.

[26]  J. Arrowsmith.  Trial watch: Phase III and submission failures: 2007–2010 , 2011, Nature Reviews Drug Discovery.

[27]  Warren R. J. D. Galloway,et al.  Drug discovery: A question of library design , 2011, Nature.

[28]  T. Ritchie,et al.  The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design? , 2009, Drug discovery today.

[29]  N. Blomberg,et al.  An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca's drug discovery programmes. , 2007, Current topics in medicinal chemistry.

[30]  Stevan W. Djuric,et al.  F1000Prime recommendation of Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. , 2010 .

[31]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[32]  2008 to 2010 , 2013 .

[33]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[34]  Supa Hannongbua,et al.  In-silico ADME models: a general assessment of their utility in drug discovery applications. , 2011, Current topics in medicinal chemistry.

[35]  M T D Cronin,et al.  A review of the electrophilic reaction chemistry involved in covalent DNA binding , 2010, Critical reviews in toxicology.

[36]  J. Gasteiger,et al.  Prediction of Aqueous Solubility of Organic Compounds by Topological Descriptors , 2003 .

[37]  M. Hann.  Molecular obesity, potency and other addictions in drug discovery , 2011 .

[38]  P. Hajduk.  Fragment-based drug design: how big is too big? , 2006, Journal of medicinal chemistry.

[39]  Graham F. Smith.  Medicinal chemistry by the numbers: the physicochemistry, thermodynamics and kinetics of modern drug design. , 2009, Progress in medicinal chemistry.

[40]  R J Riley,et al.  Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. , 2007, Current drug metabolism.

[41]  György G. Ferenczy,et al.  Enthalpic Efficiency of Ligand Binding , 2010, J. Chem. Inf. Model..

[42]  Paul D Leeson,et al.  Time-related differences in the physical property profiles of oral drugs. , 2004, Journal of medicinal chemistry.

[43]  Adrian Whitty,et al.  The resurgence of covalent drugs , 2011, Nature Reviews Drug Discovery.

[44]  György M. Keserü,et al.  The influence of lead discovery strategies on the properties of drug candidates , 2009, Nature Reviews Drug Discovery.

[45]  Ola Engkvist,et al.  Molecular Topology Analysis of the Differences between Drugs, Clinical Candidate Compounds, and Bioactive Molecules , 2010, J. Chem. Inf. Model..

[46]  Miles Congreve,et al.  Deal watch: Valuation benefits of structure-enabled drug discovery , 2011, Nature Reviews Drug Discovery.

[47]  B. Munos.  Lessons from 60 years of pharmaceutical innovation , 2009, Nature Reviews Drug Discovery.

[48]  John P. Overington,et al.  Probing the links between in vitro potency, ADMET and physicochemical parameters , 2011, Nature Reviews Drug Discovery.

[49]  Tudor I. Oprea,et al.  Is There a Difference between Leads and Drugs? A Historical Perspective , 2001, J. Chem. Inf. Comput. Sci..

[50]  J. Proudfoot,et al.  The evolution of synthetic oral drug properties. , 2005, Bioorganic & medicinal chemistry letters.

[51]  Peter Ertl,et al.  The graphical representation of ADME-related molecule properties for medicinal chemists. , 2011, Drug discovery today.

[52]  J. Hughes,et al.  Physiochemical drug properties associated with in vivo toxicological outcomes. , 2008, Bioorganic & medicinal chemistry letters.

[53]  Nigel Greene,et al.  Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies. , 2010, Bioorganic & medicinal chemistry letters.

[54]  David R Cheshire.  How well do medicinal chemists learn from experience? , 2011, Drug discovery today.

[55]  R. Morphy.  Selectively nonselective kinase inhibition: striking the right balance. , 2010, Journal of medicinal chemistry.

[56]  D. Kell,et al.  Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? , 2008, Nature Reviews Drug Discovery.

[57]  P. Verhoest,et al.  Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. , 2010, ACS chemical neuroscience.

[58]  Mladen Vinković,et al.  Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. , 2009, Journal of medicinal chemistry.

[59]  Michael S Lajiness,et al.  Assessment of the consistency of medicinal chemists in reviewing sets of compounds. , 2004, Journal of medicinal chemistry.

[60]  Emanuele Perola,et al.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. , 2010, Journal of medicinal chemistry.

[61]  Yuichi Nagahara,et al.  Are There Differences between Launched Drugs, Clinical Candidates, and Commercially Available Compounds? , 2010, J. Chem. Inf. Model..

[62]  M. Waring.  Lipophilicity in drug discovery , 2010, Expert Opinion on Drug Discovery.

[63]  Gianni Chessari,et al.  Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. , 2010, Journal of medicinal chemistry.

[64]  M. Waring.  Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower logD limits based on permeability. , 2009, Bioorganic & medicinal chemistry letters.

[65]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[66]  P. Verhoest,et al.  Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. , 2010, ACS chemical neuroscience.

[67]  A. Bender,et al.  Modeling Promiscuity Based on in vitro Safety Pharmacology Profiling Data , 2007, ChemMedChem.

[68]  A. Kalgutkar,et al.  Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity? , 2009, Chemistry & biodiversity.

[69]  M. Verdonk,et al.  A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. , 2007, Current topics in medicinal chemistry.

[70]  S. Muresan,et al.  Investigation of the relationship between topology and selectivity for druglike molecules. , 2010, Journal of medicinal chemistry.

[71]  Paul D. Leeson,et al.  Reducing the Risk of Drug Attrition Associated with Physicochemical Properties , 2010 .

[72]  W. Pitt,et al.  Heteroaromatic rings of the future. , 2009, Journal of medicinal chemistry.

[73]  Stephen D. Roughley,et al.  The Medicinal Chemist′s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates , 2011 .

[74]  A. Bender,et al.  Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off‐Target Effects from Chemical Structure , 2007, ChemMedChem.

[75]  Alexander A Alex,et al.  Fragment-based drug discovery: what has it achieved so far? , 2007, Current topics in medicinal chemistry.

[76]  John Steele,et al.  Drug-like properties: guiding principles for design - or chemical prejudice? , 2004, Drug discovery today. Technologies.

[77]  Ian A. Watson,et al.  Characteristic physical properties and structural fragments of marketed oral drugs. , 2004, Journal of medicinal chemistry.

[78]  Raimund Mannhold,et al.  Molecular Drug Properties: Measurement and Prediction , 2007 .

[79]  Dennis A. Smith.  Discovery and ADMET: Where are we now. , 2011, Current topics in medicinal chemistry.

[80]  Andrew M Davis,et al.  Components of successful lead generation. , 2005, Current topics in medicinal chemistry.

[81]  Graham F Smith,et al.  Designing drugs to avoid toxicity. , 2011, Progress in medicinal chemistry.

[82]  Paul G Wyatt,et al.  Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. , 2008, Journal of medicinal chemistry.

[83]  Stuart L. Schreiber,et al.  Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles , 2010, Proceedings of the National Academy of Sciences.

[84]  Alexander D. MacKerell,et al.  Automated Selection of Compounds with Physicochemical Properties To Maximize Bioavailability and Druglikeness , 2011, J. Chem. Inf. Model..

[85]  Richard Morphy,et al.  The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. , 2006, Journal of medicinal chemistry.

[86]  A. H. Lipkus,et al.  Structural Diversity of Organic Chemistry. a Scaffold Analysis of the Cas Registry , 2022 .

[87]  Minoru Ishikawa,et al.  Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. , 2011, Journal of medicinal chemistry.

[88]  Adrian L Gill,et al.  A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. , 2007, Current topics in medicinal chemistry.

[89]  L. Knutsen.  Drug discovery management, small is still beautiful: Why a number of companies get it wrong. , 2011, Drug discovery today.

[90]  M. Gleeson.  Generation of a set of simple, interpretable ADMET rules of thumb. , 2008, Journal of medicinal chemistry.

[91]  J. S. Carey,et al.  Analysis of the reactions used for the preparation of drug candidate molecules. , 2006, Organic & biomolecular chemistry.

[92]  Bo Nordén,et al.  Overcoming undesirable HERG potency of chemokine receptor antagonists using baseline lipophilicity relationships. , 2008, Journal of medicinal chemistry.

[93]  Michal Vieth,et al.  Dependence of molecular properties on proteomic family for marketed oral drugs. , 2006, Journal of medicinal chemistry.

[94]  Thierry Kogej,et al.  Physicochemical property profiles of marketed drugs, clinical candidates and bioactive compounds. , 2009, Bioorganic & medicinal chemistry letters.

[95]  Paul D. Leeson,et al.  Impact of ion class and time on oral drug molecular properties , 2011 .

[96]  M. Congreve,et al.  Recent developments in fragment-based drug discovery. , 2008, Journal of medicinal chemistry.

[97]  A. Hill,et al.  Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity. , 2010, Drug discovery today.

[98]  Andrew R. Leach,et al.  Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery , 2001, J. Chem. Inf. Comput. Sci..

[99]  Sorel Muresan,et al.  Analysis of in vitro bioactivity data extracted from drug discovery literature and patents: Ranking 1654 human protein targets by assayed compounds and molecular scaffolds , 2011, J. Cheminformatics.

[100]  M. Edwards,et al.  Using the Golden Triangle to optimize clearance and oral absorption. , 2009, Bioorganic & medicinal chemistry letters.

[101]  P. Hajduk,et al.  Cheminformatic tools for medicinal chemists. , 2010, Journal of medicinal chemistry.