Garry Pairaudeau

An analysis of the attrition of drug candidates from four major pharmaceutical companies

The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

Creativity, innovation and lean sigma: a controversial combination?

The application of lean sigma is gaining momentum in drug discovery and development but it remains controversial because of perceptions that process improvement will suppress much-needed creativity and innovation. We review the conditions required to support creativity and innovation and the principles and benefits of lean sigma in a drug discovery environment. We conclude that it is desirable to create a unified climate that encourages and enables both innovation and continuous improvement and that this is possible if three key tensions are handled carefully and with due respect to the needs of research. These three potential traps occur in the interpretation of standardization, the role of variation and the choice of how to use liberated capacity.

Potent Reversible Inhibition of Myeloperoxidase by Aromatic Hydroxamates

Background: Myeloperoxidase causes oxidative damage in many inflammatory diseases. Results: New substituted aromatic hydroxamates are identified as potent, selective, and reversible inhibitors of MPO. Conclusion: Binding affinities of hydroxamates to the heme pocket determine the potency of inhibition. Significance: Compounds that bind tightly to the active site of myeloperoxidase have potential as therapeutically useful inhibitors of oxidative stress. The neutrophil enzyme myeloperoxidase (MPO) promotes oxidative stress in numerous inflammatory pathologies by producing hypohalous acids. Its inadvertent activity is a prime target for pharmacological control. Previously, salicylhydroxamic acid was reported to be a weak reversible inhibitor of MPO. We aimed to identify related hydroxamates that are good inhibitors of the enzyme. We report on three hydroxamates as the first potent reversible inhibitors of MPO. The chlorination activity of purified MPO was inhibited by 50% by a 5 nm concentration of a trifluoromethyl-substituted aromatic hydroxamate, HX1. The hydroxamates were specific for MPO in neutrophils and more potent toward MPO compared with a broad range of redox enzymes and alternative targets. Surface plasmon resonance measurements showed that the strength of binding of hydroxamates to MPO correlated with the degree of enzyme inhibition. The crystal structure of MPO-HX1 revealed that the inhibitor was bound within the active site cavity above the heme and blocked the substrate channel. HX1 was a mixed-type inhibitor of the halogenation activity of MPO with respect to both hydrogen peroxide and halide. Spectral analyses demonstrated that hydroxamates can act variably as substrates for MPO and convert the enzyme to a nitrosyl ferrous intermediate. This property was unrelated to their ability to inhibit MPO. We propose that aromatic hydroxamates bind tightly to the active site of MPO and prevent it from producing hypohalous acids. This mode of reversible inhibition has potential for blocking the activity of MPO and limiting oxidative stress during inflammation.

Studies toward the synthesis of natural and unnatural dienediynes. Part 2: A practical approach to functionalised cyclopentenones

Abstract The dienediyne natural products contain a functionalised dihydroxylated cyclopentane motif. A critical evaluation of the methods for the preparation and rearrangements of pyranones to give 4,5-dihydroxylated cyclopentenones is presented.

A Practical Method for Targeted Library Design Balancing Lead-like Properties with Diversity

Choosing the right compounds to synthesise from large virtual combinatorial libraries is a current challenge for the pharmaceutical industry. Herein we describe a highly optimised method that aligns lead‐like properties with compound diversity. The methods are illustrated by considering a two‐dimensional library based on the interesting spirocyclic bis‐azetidine template.

Stereoselective synthesis of polyfunctionalised hydroxylated cyclopentanes from dihydroxylated 2-cyclopentenone derivatives

Abstract Dihydroxylated cyclopentenones can be readily synthesised via a base mediated isomerisation reaction. These species and their derivatives can be used to provide a wide range of synthetically useful intermediates by participation in a variety of stereoselective transformations. These include: nucleophilic and conjugate addition, intermolecular cycloaddition, intramolecular free-radical cyclisation and palladium mediated coupling reactions.

Design driven HtL: The discovery and synthesis of new high efficacy β2-agonists

The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

Design-driven LO: The discovery of new ultra long acting dibasic β2-adrenoceptor agonists

Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.

Towards a hit for every target

Technological advances coupled with novel collaborative strategies for compound sourcing and management are poised to transform the utility of high-throughput screening.

From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.