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
Citations
More filters
Journal ArticleDOI
Strategies for the Design of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Lessons from the Development of Seven Representative Paradigms
TL;DR: Transcriptase Inhibitors: Lessons from the Development of Seven Representative Paradigms
Journal ArticleDOI
Where Do Recent Small Molecule Clinical Development Candidates Come From
Dean G. Brown,Jonas Boström +1 more
TL;DR: The majority of clinical candidates were found to be structurally very different from their starting point and were more complex, and several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.
Journal ArticleDOI
Identification of NVP-TNKS656: The Use of Structure–Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor
Michael Shultz,Atwood K. Cheung,Christina A. Kirby,Brant Firestone,Jianmei Fan,Chen Christine Hiu-Tung,Zhouliang Chen,Donovan N. Chin,Dipietro Lucian,Aleem Fazal,Yun Feng,Pascal D. Fortin,Ty Gould,Bharat Lagu,Lei Huangshu,Francois Lenoir,Dyuti Majumdar,Etienne Ochala,Palermo Mark G,Pham Ly Luu,Minying Pu,Troy Smith,Travis Stams,Ronald Tomlinson,B. Barry Touré,Michael Scott Visser,Run Ming Wang,Nigel J. Waters,Wenlin Shao +28 more
TL;DR: NVP-TNKS656 was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model and is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.
Journal ArticleDOI
Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors
TL;DR: In this article, the authors analyzed the properties of iPPIs in terms of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes.
Journal ArticleDOI
Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds.
TL;DR: It is shown that aqueous solubility, Caco-2 permeability, plasma protein binding, human ether-a-go- go-related potassium channel protein inhibition, and CYP3A4 (CYP = cytochrome P450) inhibition are influenced by the molecular topology.
References
More filters
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.