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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Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action
TL;DR: This review will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic.
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Leitstruktur‐orientierte Synthese: eine Alternative für die Synthesechemie
TL;DR: In this paper, the authors present the Konzept der Leitstruktur-orientierten Synthese and the Moglichkeit, durch ihre Anwendung das Spektrum and die Qualitat von Verbindungen fur die Entwicklung neuer Medikamente zu erhohen.
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Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.
Benjamin Fauber,Alberto Gobbi,Kirk Robarge,Aihe Zhou,Adrian Barnard,Jianhua Cao,Yuzhong Deng,Celine Eidenschenk,Christine Everett,Arunima Ganguli,Julie Hawkins,Adam R. Johnson,Hank La,Maxine Norman,Gary Salmon,Susan Summerhill,Wenjun Ouyang,Wei Tang,Harvey Wong +18 more
TL;DR: The favorable potency, selectivity, and physiochemical properties of G NE-0946 and GNE-6468, in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.
Journal ArticleDOI
Discovery and Characterization of 6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, Irdabisant): A Potent, Selective Histamine H3 Receptor Inverse Agonist
Robert L. Hudkins,Rita Raddatz,Ming Tao,Joanne R. Mathiasen,Lisa D. Aimone,Nadine C. Becknell,Prouty Catherine P,Lars J. S. Knutsen,Mehran Yazdanian,Gilbert Moachon,Mark A. Ator,John P. Mallamo,Michael J. Marino,Edward R. Bacon,Michael Williams +14 more
TL;DR: 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins and it weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go- go-related gene.
Journal ArticleDOI
Big pharma screening collections: more of the same or unique libraries? The AstraZeneca–Bayer Pharma AG case
Thierry Kogej,Niklas Blomberg,Peter J. Greasley,Stefan Mundt,Mikko J. Vainio,Jens Schamberger,Georg Schmidt,Jörg Hüser +7 more
TL;DR: Results revealed a low overlap between both collections in terms of compound identity and similarity, emphasizing the value of screening multiple compound collections to expand the chemical space that can be accessed by high-throughput screening (HTS).
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.