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
Clear Castable Polyurethane Elastomer for Fabrication of Microfluidic Devices
Karel Domansky,Daniel C. Leslie,James McKinney,Jacob P. Fraser,Josiah Sliz,Tiama Hamkins-Indik,Geraldine A. Hamilton,Anthony Bahinski,Donald E. Ingber,Donald E. Ingber,Donald E. Ingber +10 more
TL;DR: An attractive alternative material is described that is similar to PDMS in terms of optical transparency, flexibility and castability, but that is also resistant to absorption of small hydrophobic molecules.
Journal ArticleDOI
Sulfonimidamides in Medicinal and Agricultural Chemistry.
Praveen K. Chinthakindi,Tricia Naicker,Niranjan Thota,Thavendran Govender,Hendrik G. Kruger,Per I. Arvidsson,Per I. Arvidsson +6 more
TL;DR: Recent developments to showcase the promise of the sulfonamide functional group, which is rapidly gaining popularity as a novel functional group among synthetic chemists involved in the design of biologically active compounds for both pharmaceutical and agrochemical applications.
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Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations.
TL;DR: This work systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation and found that about 94% of the native poses were maintained stable during the simulations, which suggests that MD simulations are accurate enough to judge most experimental binding poses as stable properly.
Journal ArticleDOI
Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor
Keith F. McDaniel,Le Wang,Todd N. Soltwedel,Steven D. Fidanze,Lisa A. Hasvold,Dachun Liu,Robert A. Mantei,John K. Pratt,George S. Sheppard,Mai H. Bui,Emily J. Faivre,Xiaoli Huang,Leiming Li,Xiaoyu Lin,Rongqi Wang,Scott E. Warder,Denise Wilcox,Daniel H. Albert,Terrance J. Magoc,Ganesh Rajaraman,Chang H. Park,Charles W. Hutchins,Jianwei J. Shen,Rohinton P. Edalji,Chaohong C. Sun,Ruth L. Martin,Wenqing Gao,Shekman Wong,Guowei Fang,Steven W. Elmore,Yu Shen,Warren M. Kati +31 more
TL;DR: The discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.
Journal ArticleDOI
Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals
TL;DR: A class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates of biaryls decorated with polar and delicate functionalities are introduced.
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.