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
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Journal ArticleDOI
Discovery of 2H-Chromen-2-one Derivatives as G Protein-Coupled Receptor-35 Agonists
Lai Wei,Jixia Wang,Xiuli Zhang,Xiuli Zhang,Ping Wang,Yaopeng Zhao,Jiaqi Li,Tao Hou,Lala Qu,Shi Liying,Xinmiao Liang,Xinmiao Liang,Ye Fang +12 more
TL;DR: This study provides a novel series of GPR35 agonists, and 6-Bromo-7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one (50) was found to be the most potent G PR35 agonist with an EC50 of 5.8 nM, and compound 50 may be a powerful tool to study GPR 35.
Journal ArticleDOI
2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1γ) inhibitors
Zihao Hua,Xin Huang,Howard Bregman,Nagasree Chakka,Erin F. DiMauro,Elizabeth M. Doherty,Jonathan T. Goldstein,Hakan Gunaydin,Hongbing Huang,Stephanie J. Mercede,John Newcomb,Vinod F. Patel,Susan M. Turci,Jie Yan,Cindy Wilson,Matthew W. Martin +15 more
TL;DR: In this paper, the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity.
Patent
1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
Jose Maria Cid-Nunez,Andrés Avelino Trabanco-Suárez,Gregor James Macdonald,Guillaume Albert Jacques Duvey,Robert Johannes Lütjens,Terry Patrick Finn +5 more
TL;DR: In this article, a method of treating, ameliorating, or controlling a condition in a mammal, including a human, wherein the condition is selected from the group consisting of anxiety disorders, psychotic disorders, substance-dependence related disorders, mood disorders, epilepsy or convulsive disorders, idiopathic Parkinson's disease, and Alzheimer's disease.
Journal ArticleDOI
Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs
Adriana Port,Magda Bordas,Raquel Enrech,Rosalia Pascual,Martí Rosés,Clara Ràfols,Xavier Subirats,Elisabeth Bosch +7 more
TL;DR: An excellent equivalence has been found between log Po/w values obtained by shake‐flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high‐throughput is required.
Journal ArticleDOI
Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase.
Benjamin Fauber,Peter S. Dragovich,Jinhua Chen,Laura Corson,Charles Z. Ding,Charles Eigenbrot,Sharada Labadie,Shiva Malek,David A. Peterson,Hans E. Purkey,Kirk Robarge,Steve Sideris,Mark Ultsch,Binqing Wei,Ivana Yen,Qin Yue,Aihe Zhou +16 more
TL;DR: A series of 3,6-disubstituted dihydropyrones identified as inhibitors of human lactate dehydrogenase (LDH)-A led to improvements in LDHA potency, resulting in the identification of 51 (IC50=30 nM).
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.