Design and Synthesis of a Maximally Diverse and Druglike Screening Library Using REM Resin Methodology

Barn, David R.; Caulfield, Wilson; Cowley, Phillip M.; Dickins, Rachel S.; Bakker, Wouter; McGuire, Ross; Morphy, J. Richard; Rankovic, Zoran; Thorn, M

doi:10.1021/cc000096t

Cited by 19 publications

(18 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was concluded that orally active drugs with passive transcellular transport should not exceed a PSA of 120 Å 2 , and a 60-70 Å 2 for appropriate BBB permeability. MW was identified as a good descriptor of BBB penetration [66,67], and applied in fact as a key property filter together with logP in testing a 3042 compound screening library [68] for CNS-compatibility. Chico et al [69] claimed that kinase inhibitor drugs for CNS indications required a modification of the property limits set by the Ro5.…”

Section: Specific Drug-likenessmentioning

confidence: 99%

Molecular Property Filters Describing Pharmacokinetics and Drug Binding

García-Sosa

Maran

Hetényi

2012

CMC

View full text Add to dashboard Cite

Drug-target binding affinity and pharmacokinetics are equally important factors of drug design. Simple molecular properties such as molecular size have been used as pharmacokinetic and/or drug-likeness filters during chemical library design and also correlated with binding affinity. In the present study, current property filters are reviewed, a collection of their optimal values is provided, and a statistical framework is introduced allowing calibration of their selectivity and sensitivity for drugs. The role of ligand efficiency indices in drug design is also described. It is concluded that the usefulness of property filters of molecular size and lipophilicity is limited as predictors of general drug-likeness. However, they demonstrate increased performance in specific cases, e.g. in central nervous system diseases, emphasizing their future importance in specific, disease-focused library design instead of general drug-likeness filtering.

show abstract

Section: Specific Drug-likenessmentioning

confidence: 99%

Molecular Property Filters Describing Pharmacokinetics and Drug Binding

García-Sosa

Maran

Hetényi

2012

CMC

View full text Add to dashboard Cite

show abstract

“…an increased likelihood of the compounds to cross the BBB [72]. Organon, for example, have published an interesting approach for the design of an information-rich library involving state-of-the-art knowledge on computational tools to predict CNS penetration, which was the basis for the purpose-built synthesis of an HTS compound library privileged for CNS programs [73]. The ongoing process of refining the computational approaches to the prediction of CNS penetration and blood-brain distribution [74][75][76][77][78][79][80][81][82][83][84][85][86][87] will be the way forward to a more successful virtual screening and design of CNS-like compound libraries.…”

Section: Cns Programsmentioning

confidence: 99%

The Role of Blood-Brain Barrier Studies in the Pharmaceutical Industry

Reichel¹

2006

CDM

127

View full text Add to dashboard Cite

The blood-brain barrier (BBB) remains one of the greatest challenges for the discovery and development of treatments for CNS disorders, which to this day remains one of the riskiest disease areas in terms of clinical success rates. Although the BBB is currently seen predominantly as a permeability obstacle for CNS drug delivery, it is becoming increasingly clear that the BBB has many more implications for the pharmaceutical industry impacting on CNS pharmacology and pathology, CNS pharmacokinetics and pharmacodynamics, and adverse CNS effects, to name but a few areas. The present review does not intend to summarize the activities in the field of BBB research per se, which has been accomplished by a number of excellent recent reviews, but instead to provide an overview of the role of BBB studies from a pharmaceutical industry perspective. This review will elaborate on the specific needs in terms of BBB-related issues across the different drug discovery and development phases, i.e. target identification and validation, lead generation and optimization, candidate selection and profiling, preclinical development and clinical studies. The specific approaches taken will be discussed in terms of specific requirements, questions to be asked, feasibility, interpretability, and impact. It becomes clear that few of the existing BBB models fully meet the requirements of the industrialized drug discovery process, highlighting the need for an array of new or modified tools and approaches that are more effective in helping make decisions which are more specifically tailored to the various stages of the lengthy process from target to the clinic. In looking at the numerous ongoing activities in the area of BBB research from the drug discovery and development point of view, an attempt has been made to place a stronger emphasis on the applicability of particular techniques and approaches, to identify gaps and areas for future activities. In order to materialize the considerable knowledge gained in recent years, the review is intended to foster an increased awareness of the need to better integrate basic academic research with the specific requirements of the pharmaceutical industry for the search of effective and safe new CNS medicines.

show abstract

“…General procedure for the Suzuki reaction using triflates [121]: The following procedure employs K 2 CO 3 , which may cause hydrolysis of labile esters within the coupling components.…”

Section: Methodsmentioning

confidence: 99%

“…These mixtures of solids can then be distrib- Merrifield [95] Br Ph, Ph with EDG in 2-and 3-positions, 3-thiophenyl, 2-thiophenyl 0.05 equiv. Pd(PPh3) 4 Boronate resin [55] REM resin [121] Ph with EWG and EDG in 2, 3, 4 position 4 equiv. Ph with EWG in 2, 3, and 4-positions; EDG in 4-or 2-position of naphthyl 0.1 equiv.…”

mentioning

confidence: 99%