The creation and characterisation of a National Compound Collection: the Royal Society of Chemistry pilot.

We present a summary of the National Compound Collection (NCC) pilot; which harvested chemical structure data from 746 publicly-available PhD theses to create an enhanced database of diverse and interesting (largely organic) molecular entities. The database comprised ∼75 000 structure entries, of which 70% were new to ChemSpider at the time of upload. The dataset was evaluated for structural uniqueness by twelve external drug discovery groups from the pharmaceutical, biotech, academic and not-for-profit sectors. These partners generated data reported here comparing the NCC pilot with their in-house compound collections. The proportion of NCC structures considered to be useful for drug discovery ranged from 5-80% depending on the strictness of the filters used; most interestingly from a drug discovery standpoint ∼13k NCC compounds (18% of the NCC) passed the filters and were of good diversity. These compounds are quite different from those that are already present in the screening collections but not so different that they are no longer considered to be drug-like. In general, the drug discovery teams would consider these compounds to be high value molecules for inclusion in their screening collections. This pilot addressed the potential value of unpublished data and explored the practicalities of large-scale data extraction, to inform both retrospective and prospective extraction of chemical data from theses.

Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: in vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.

Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.

Nucleotide competing reverse transcriptase inhibitors: discovery of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.

A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.

Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors.

Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.

MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.

HTS promiscuity analyses for accelerating decision making.

Frequent hitters are compounds that are detected as a "hit" in multiple high-throughput screening (HTS) assays. Such behavior is specific (e.g., target family related) or unspecific (e.g., reactive compounds) or can result from a combination of such behaviors. Detecting such hits while predicting the underlying reason behind their promiscuous behavior is desirable because it provides valuable information not only about the compounds themselves but also about the assay methodology and target classes at hand. This information can also greatly reduce cost and time during HTS hit profiling. The present study exemplifies how to mine large HTS data repositories, such as the one at Boehringer Ingelheim, to identify frequent hitters, gain further insights into the causes of promiscuous behavior, and generate models for predicting promiscuous compounds. Applications of this approach are demonstrated using two recent large-scale HTS assays. The authors believe this analysis and its concrete applications are valuable tools for streamlining and accelerating decision-making processes during the course of hit discovery.

Revealing atropisomer axial chirality in drug discovery.

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.

Development of specific "drug-like property" rules for carboxylate-containing oral drug candidates.

The carboxylate moiety is an important pharmacophore in the medicinal chemist's arsenal and is sometimes an irreplaceable functionality in drug-target interactions. Thus, practical guidance on its use in the most optimized manner would be a welcome addition to rational drug design. 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. Our main objective was to identify features specific to COOH-containing oral drugs that could be converted into simple rules delineating the boundaries within which prospective COOH-containing chemical series and COOH-containing drug candidates would be reasonably expected to possess properties suitable for oral administration. These specific "drug-like" property rules include molecular weight, the number of rotatable bonds, the number of hydrogen bond donors and acceptors, predictions of lipophilic character (calculated log P and log D values), topological polar surface area (TPSA), and the pK(a) value of the carboxylate moiety. Similar to the various sets of criteria that have emerged over the past decade and which have significantly reshaped the way medicinal chemists think about preferred drug chemical space, we propose these specific COOH "drug-like" property rules as a guide for the design of superior COOH-containing drug candidates and as a tool to better manage the liabilities generally associated with the presence of a COOH moiety.

Current parallel chemistry principles and practice: application to the discovery of biologically active molecules.

This article describes the use of parallel chemistry techniques for drug discovery, based on publications from January 2006 to December 2008. Chemical libraries that yielded active compounds across a range of biological targets are presented, together with synthetic details when appropriate. Background information for the biological targets involved and any SAR that could be discerned within members of a library series also is discussed. New technological developments, as applied to library design and synthesis and, more generally, in the discovery of biologically active entities, are highlighted. In addition, the likely future directions for parallel chemistry in its ability to impact upon drug discovery are also presented.

The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements.

For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.

From lead to preclinical candidate: optimization of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV.

A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.

Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.

Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.

Value networks identify innovation in 21st century pharmaceutical research.

To answer the clarion call for more innovation and productivity in Pharmaceutical research, the application of the ValueNet Work methodology to the indication switch for Viagra, from an anti-hypertensive to the treatment for male erectile dysfunction, was undertaken to ascertain the usefulness of this approach for Pharmaceutical research in identifying both tangible and intangible value drivers, and for the identification of strong value-creating relationships within this research area. Through the identification of participants, tangible and intangible deliverables, and the analysis of their interactions in the indication switch for Viagra, an insight into value drivers for the Pharmaceutical industry was revealed that has an impact on Pharmaceutical innovation and productivity. This methodology, in pinpointing value inflection points holds promise in analysing other aspects of research.

Expediting drug discovery: recent advances in fast medicinal chemistry--optimization of hits and leads.

This article reviews the literature from January 2004 to January 2006 relating to the use of parallel chemistry compound libraries in drug discovery. Examples of libraries that have yielded active compounds across a range of biological targets are presented, together with synthetic details where relevant. The background of the biological target, and any structure-activity relationship that can be discerned from members of a library series, are also commented upon. A brief discussion of new technological developments in library design and synthesis, and likely future directions for parallel chemistry in the context of drug discovery, is also presented.

The impact of parallel chemistry in drug discovery.

With the application of parallel synthesis of single compounds to drug-discovery efforts, improvements in the efficiency of synthesis are possible. However, for improvements to occur in effective drug design - a critical requirement to increase productivity in the modern pharmaceutical industry - the implementation of in silico design hypotheses that incorporate comprehensive information on a target, including considerations of absorption, distribution, metabolism and excretion, is also necessary. Concomitantly, the use of automated methods of synthesis and purification is also required to improve drug design. Combining all of these elements allows the possibility to uncover unique insights into a biological target quickly and to therefore accelerate the rate of drug discovery.

The reversed binding of beta-phenethylamine inhibitors of DPP-IV: X-ray structures and properties of novel fragment and elaborated inhibitors.

The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.

Synthesis of (+/-)-secosyrin 1 and a formal synthesis of (-)-secosyrin 1.

[reaction: see text] A short synthesis of (+/-)-secosyrin 1 is presented that starts from an electron-deficient furan; reductive alkylation under Birch conditions gives rapid access to the natural product skeleton. Two aspects of stereoselectivity are explored, the first being directed dihydroxylation of a homoallylic alcohol. Second, the facial selectivity obtained during reduction of a highly substituted cyclic ketone was examined. Finally, our synthesis was rendered enantioselective by the reduction of a furan bearing a chiral auxiliary.

Purification strategies for combinatorial and parallel chemistry.

This review surveys the methods developed for the purification of intermediates and final compounds originating from parallel and combinatorial chemistry. Included will be reviews of polymer-assisted purification, liquid-phase combinatorial chemistry, fluorous synthesis, liquid-liquid and solid-phase extraction, reverse-phase HPLC and supercritical fluid chromatography. A critique of each method is given, highlighting the methodologies strengths and weaknesses.