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
Sulfonimidamide in medizinischer Chemie und Agrochemie
Praveen K. Chinthakindi,Tricia Naicker,Niranjan Thota,Thavendran Govender,Hendrik G. Kruger,Per I. Arvidsson,Per I. Arvidsson +6 more
TL;DR: The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, with some 500 compounds that has overcome both the pharmacological and regulatory hurdles that precede studies in humans.
Journal ArticleDOI
Development of specific "drug-like property" rules for carboxylate-containing oral drug candidates.
TL;DR: Key physicochemical and ADMET‐PK properties from a dataset of drugs containing a carboxylate (COOH) moiety were assembled and compared with those of a broader, general drug dataset to identify features specific to COOH‐containing oral drugs that could be converted into simple rules delineating the boundaries within which prospective COO h‐containing chemical series and COOh‐containing drug candidates would be reasonably expected to possess properties suitable for oral administration.
Journal ArticleDOI
Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment.
Catherine J Hutchings,G. Cseke,Greg J. Osborne,Jeanette Woolard,Andrei Zhukov,Markus Koglin,Ali Jazayeri,Jahnavi Pandya-Pathak,Christopher J. Langmead,Stephen J. Hill,Malcolm Peter Weir,Fiona H. Marshall +11 more
TL;DR: The anti-β1AR mAbs only demonstrated agonist activity when in dimeric antibody format, but not as the monomeric Fab format, suggesting that agonist activation may be mediated through promoting receptor dimerization.
Journal ArticleDOI
Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies
TL;DR: The five FDA-approved PI 3-kinase inhibitors produce significant on-target toxicities, more so than many approved protein kinase antagonists.
Journal ArticleDOI
Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor.
Laura J. Chambers,Alexander J. Stevens,Andrew P. Moses,Anton D. Michel,Daryl S. Walter,David John Davies,Livermore David,Elena Fonfria,Emmanuel Hubert Demont,Mythily Vimal,P. Theobald,Paul John Beswick,Robert Gleave,Shilina Roman,Stefan Senger +14 more
TL;DR: Structural-activity relationships of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
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.