Drug-like properties: guiding principles for design – or chemical prejudice?

Leeson, Paul D.; Davis, A. M.; Steele, John W.

doi:10.1016/j.ddtec.2004.11.005

Cited by 76 publications

(37 citation statements)

References 44 publications

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“…Physicochemical properties associated with druglike molecules have been described previously (7,11,12). The well-known rule of five (RO5) was derived in 1997 from a database of clinical candidates that had reached phase II trials or further (13).…”

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confidence: 99%

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Wager

Chandrasekaran

Hou

et al. 2010

ACS Chem. Neurosci.

409

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As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

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mentioning

confidence: 99%

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Wager

Chandrasekaran

Hou

et al. 2010

ACS Chem. Neurosci.

409

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show abstract

“…Much emphasis is now placed on addressing the physicochemical properties of small molecules early in the current drug discovery paradigm dominated by HTS [10]. Oprea, for example, advocated screening libraries comprised of 'lead-like' or 'reduced complexity' sets with even more stringent physicochemical profiles than the Rule of 5 [11,12].…”

Section: Molecular Librariesmentioning

confidence: 99%

Merging structural biology with chemical biology: Structural Chemistry at Eskitis

et al. 2010

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This review introduces the Structural Chemistry Program at Griffith University's Eskitis Institute, and provides a brief overview over its current and future research portfolio. Capitalising on the co-location with the Queensland Compound Library (QCL), Australia's only small molecule repository, our laboratory investigates the structure and function of proteins with the aim of learning about their molecular mechanisms. Consequently, these studies also feed into drug discovery and design. The thematic focus of our Program is on proteins involved in infection, inflammation and neurological diseases, and this review highlights a few of our recent research efforts in this area. Queensland Government enabled construction of the second of the two buildings which commenced in late 2006. The building became fully operational in April 2008. About the Structural Chemistry ProgramOur Program was established in 2006 as one of ten research programs of the newly formed Eskitis Institute. Our laboratory complements the research portfolio of the Institute by providing structural information to understand protein mechanisms at the molecular level. To improve the knowledge of the molecular mechanisms of diseases as well as to identify possible sites of interference, one needs to have a solid understanding of the structure and functions of proteins, and their interactions with ligands, target proteins and membranes. With protein crystallography on the one hand and a variety of biophysical methods on the other, our laboratory investigates structure, shape and properties of proteins and establishes structure-function relationships to obtain a rationale for future therapeutic applications. This includes

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“…By contrast, three of the five fragments appearing in newer drugs that are not reflected in older drugs are related to homophenylalanine, a fragment common to many ACE inhibitors, such as enalapril, that have been launched in the past 20 years. As we and others have shown [1,17], however, the physical property differences for new vs old oral drugs are generally very small. These fragment differences, notably smaller than for the other comparisons, likely reflect target-related differences.…”

Section: Analysis Of Similarities Of Different Drug Data Sets Based Omentioning

confidence: 99%

Structural Fragments in Marketed Oral Drugs

Vieth

Siegel

2006

Fragment‐based Approaches in Drug Discovery

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Drug-like properties: guiding principles for design – or chemical prejudice?

Cited by 76 publications

References 44 publications

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Merging structural biology with chemical biology: Structural Chemistry at Eskitis

Structural Fragments in Marketed Oral Drugs

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