Drug-likeness : what does it mean ?

Drug-like space might be more densely populated with orally available compounds than the remaining chemical space, but lead optimization can still occur outside this space. Oral drug space is more dynamic than the relatively static drug-like space. As new targets emerge and optimization tools advance the oral drug space might expand. Lead optimization protocols are becoming more complex with greater optimization needs to be satisfied, which consequently could change the role of drug-likeness in the process. Whereas drug-like space should usually be explored preferentially, it can be easier to find oral drugs for certain targets in the nondrug-like space.

[1]  T. Berg Small-molecule inhibitors of protein-protein interactions. , 2008, Current opinion in drug discovery & development.

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

[3]  John P. Overington,et al.  How many drug targets are there? , 2006, Nature Reviews Drug Discovery.

[4]  G. Feuerstein,et al.  Carvedilol case history: the discovery and development of the first β-blocker for the treatment of congestive heart failure , 2006, Expert opinion on drug discovery.

[5]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[6]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

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

[8]  J. Ermolieff,et al.  Protein tyrosine phosphatase 1B inhibitors for diabetes , 2002, Nature Reviews Drug Discovery.

[9]  Franco Lombardo,et al.  Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. , 2002, Journal of medicinal chemistry.

[10]  Drug Truths: Dispelling the Myths About Pharma R&D , 2009 .

[11]  J. Sikorski Oral cholesteryl ester transfer protein (CETP) inhibitors: a potential new approach for treating coronary artery disease. , 2006, Journal of medicinal chemistry.

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

[13]  C. Tse,et al.  ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. , 2008, Cancer research.

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

[15]  Gang Liu,et al.  Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. , 2003, Journal of medicinal chemistry.

[16]  Jonathan C. Fuller,et al.  Predicting druggable binding sites at the protein-protein interface. , 2009, Drug discovery today.

[17]  John P. Overington,et al.  Can we rationally design promiscuous drugs? , 2006, Current opinion in structural biology.

[18]  Michael Williams Perseverance furthers? The role of the drug hunter in the postgenomic era. , 2008, Current opinion in investigational drugs.

[19]  Pedro Cuatrecasas,et al.  Drug discovery in jeopardy. , 2006, The Journal of clinical investigation.

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

[21]  Richard Morphy,et al.  The physicochemical challenges of designing multiple ligands. , 2006, Journal of medicinal chemistry.

[22]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[23]  V. Stella,et al.  Prodrug strategies to overcome poor water solubility. , 2007, Advanced drug delivery reviews.

[24]  B. Roth,et al.  Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia , 2004, Nature Reviews Drug Discovery.

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

[26]  D. Wong,et al.  The Discovery of Fluoxetine Hydrochloride (Prozac) , 2005, Nature Reviews Drug Discovery.

[27]  Nader Fotouhi,et al.  Lead generation: reality check on commonly held views , 2008, Expert opinion on drug discovery.

[28]  K. Lackey Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. , 2006, Current topics in medicinal chemistry.

[29]  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..

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

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

[32]  J. Ménard,et al.  The difficult conception, birth and delivery of a renin inhibitor: controversies around aliskiren. , 2007, Journal of hypertension.

[33]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[34]  M. Weatherall An end to the search for new drugs? , 1982, Nature.

[35]  D. Roden Antiarrhythmic drugs: past, present, and future. , 2004, Heart rhythm.

[36]  Richard Morphy,et al.  Fragments, network biology and designing multiple ligands. , 2007, Drug discovery today.

[37]  G. Grass,et al.  Effect of diverse datasets on the predictive capability of ADME models in drug discovery , 2001 .

[38]  Cele Abad-Zapatero,et al.  A sorcerer's apprentice and The Rule of Five: from rule-of-thumb to commandment and beyond. , 2007, Drug discovery today.

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

[40]  Barrie Wilkinson,et al.  Drug discovery beyond the 'rule-of-five'. , 2007, Current opinion in biotechnology.