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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Gold/Acid‐Co‐catalyzed Direct Microwave‐Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides
TL;DR: The gold-acid-co-catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved.
Journal ArticleDOI
ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors
Upul K. Bandarage,Jingrong Cao,Jon H. Come,John J. Court,Huai Gao,Marc Jacobs,Craig Marhefka,Suganthi Nanthakumar,Jeremy Green +8 more
TL;DR: Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.
Journal ArticleDOI
Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.
Katherine Louise Jones,Dominic M. Beaumont,Sharon G. Bernard,Rino A. Bit,Simon P. Campbell,Chun-wa Chung,Leanne Cutler,Emmanuel Hubert Demont,Kate Dennis,Laurie J. Gordon,James Gray,Michael V. Haase,Antonia J. Lewis,Scott McCleary,Darren Jason Mitchell,Susanne M. Moore,Nigel J. Parr,Olivia J. Robb,Nicholas Smithers,Peter Ernest Soden,Colin J. Suckling,Simon Taylor,Ann Louise Walker,Robert J. Watson,Rab K. Prinjha +24 more
TL;DR: In this paper, the structure and property-based optimization of the in vivo tool molecule I-BET151 toward the Bromodomain and extra terminal (BET) family of proteins is described.
Journal ArticleDOI
An Approach of Computer-Aided Drug Design (CADD) Tools for In Silico Pharmaceutical Drug Design and Development
TL;DR: The CADD centre was created to foster collaborative research between biologist, biophysicists, structural biologists and computational scientists to discover novel chemical entities with the potential to be developed into novel therapeutic agents.
Journal ArticleDOI
Spirocyclic ureas: Orally bioavailable 11β-HSD1 inhibitors identified by computer-aided drug design
Colin M. Tice,Wei Zhao,Zhenrong Xu,Salvacion Cacatian,Robert D. Simpson,Yuanjie Ye,Suresh B. Singh,Brian M. McKeever,Peter Lindblom,Joan Guo,Paula Krosky,Barbara A. Kruk,Jennifer Berbaum,Richard K. Harrison,Judith J. Johnson,Yuri Bukhtiyarov,Reshma Panemangalore,Boyd B. Scott,Yi Zhao,Joseph G. Bruno,Linghang Zhuang,Gerard McGeehan,Wei He,David A. Claremon +23 more
TL;DR: Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro.
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.