Journal ArticleDOI
The influence of drug-like concepts on decision-making in medicinal chemistry
TLDR
Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.Abstract:
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.read more
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Journal ArticleDOI
Size estimation of chemical space: how big is it?
TL;DR: This work aims to estimate the size of organic chemical space and its sub‐regions, i.e. drug‐likechemical space and known drug space (KDS), and to establish a rough ellipsoidal model for this space.
Journal ArticleDOI
Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.
Nadjet Rezki,Meshal A. Almehmadi,Saleh Ihmaid,Ahmed M. Shehata,Abdelsattar M. Omar,Hany E.A. Ahmed,Hany E.A. Ahmed,Mohamed Reda Aouad +7 more
TL;DR: Novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors are introduced and the results indicate that the newly discovered inhibitors have significant potential for anticancer treatment.
Journal ArticleDOI
Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases
Adrian L. Smith,Noel D'angelo,Yunxin Y. Bo,Shon Booker,Victor J. Cee,Brad Herberich,Fang-Tsao Hong,Claire L. M. Jackson,Brian A. Lanman,Longbin Liu,Nobuko Nishimura,Liping H. Pettus,Anthony B. Reed,Seifu Tadesse,Nuria A. Tamayo,Ryan Wurz,Kevin Yang,Kristin L. Andrews,Douglas A. Whittington,John D. McCarter,Tisha San Miguel,Leeanne Zalameda,Jian Jiang,Raju Subramanian,Erin L. Mullady,Sean Caenepeel,Daniel J. Freeman,Ling Wang,Nancy Zhang,Tian Wu,Paul E. Hughes,Mark H. Norman +31 more
TL;DR: Compound 54 was identified as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases and demonstrated a robust PD-PK relationship inhibiting thePI3K/Akt pathway in vivo in a mouse model.
Journal ArticleDOI
Kinetic efficiency: the missing metric for enhancing compound quality?
TL;DR: This work proposes another metric, kinetic efficiency, that may be used pragmatically to help identify those compounds displaying differentiated kinetic behaviour, which has the potential to improve decision-making in drug discovery leading to higher quality compounds and series.
Journal ArticleDOI
Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone.
Pei-Pei Kung,Piet-Jan Sinnema,Paul G. Richardson,Michael J. Hickey,Ketan S. Gajiwala,Fen Wang,Buwen Huang,Guy A. McClellan,Jeff Wang,Karen A. Maegley,Simon Bergqvist,Pramod P. Mehta,Robert Steven Kania +12 more
TL;DR: A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures that bind in a deep pocket of the HSp90 enzyme that is partially comprised by residues Asn51 and Ser52 to lead to significant improvements in inhibitor potency.
References
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Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Molecular properties that influence the oral bioavailability of drug candidates.
Daniel F. Veber,Stephen R. Johnson,Hung-Yuan Cheng,Brian R. Smith,Keith W. Ward,Kenneth D. Kopple +5 more
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Journal ArticleDOI
Can the pharmaceutical industry reduce attrition rates
Ismail Kola,John Landis +1 more
TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Book
The Merck index
TL;DR: This CD-ROM provides the tools to draw structures and then search for them, and presents over 10,000 monographs which detail chemicals, drugs and biologicals, and describe a single substance or small group of related compounds.
Journal ArticleDOI
Lead- and drug-like compounds: the rule-of-five revolution.
TL;DR: This topic is explored in terms ofDrug-like physicochemical features, drug-like structural features, a comparison of drug- like and non-drug-like in drug discovery and a discussion of how drug-Like features relate to clinical success.