Jeremy J. Edmunds

Cheminformatic Tools for Medicinal Chemists

IntroductionCheminformatics can be broadly described as any attempttousechemicalinformationtoinfertherelationshipsbetweenor attributes of chemical structures. From a drug discoveryperspective, cheminformatic principles can be applied fromthe earliest stages of lead discovery (e.g., chemical similarityand library design) to lead optimization (e.g., QSAR studies)through to preclinical and clinical development (e.g., predic-tive toxicology). The popularity of cheminformatics and itsuse in academia and the pharmaceutical industry can beappreciated from the fact that at least five scientific journalsexist almost exclusively dedicated to the field (The Journal ofCheminformatics, The Journal of Chemical Information andModeling, The Journal of Computer-Aided Molecular Design,Molecular Bioinformatics,andQSAR and CombinatorialScience), and more than 15000 scientific journal articles havebeen published during just the last 5 years that describecheminformatic research. This intense interest in cheminfor-matics stems from the promise that, if underlying relation-ships between a given chemical structure and a host ofbiological end points exist and can be elucidated, drug dis-covery timelines can be significantly reduced. Given thepressure on the pharmaceutical industry to increase produc-tivity while decreasing costs, prior knowledge of which mole-cules have the highest probability of success (or at leastknowing which molecules are likely to fail) is worthy ofvigorous pursuit.Over the past decade there have been several significantadvancements in our understanding and application of che-minformatic principles. Approaches to measuring and com-paring chemical information have become both moresophisticated and accessible. For example, two of the mostpowerfulchemicalsimilaritymeasures(two-dimensional(2D)extended connectivity fingerprints and three-dimensional(3D) shape and electrostatic overlays) are available in user-friendly software packages from Scitegic (Accelrys) andOpeneye Scientific Software. Multiple methods for under-standing and predictingbioactivity have proven their robust-ness,includingpartialleast-squares(PLS),geneticalgorithms,Bayesian analyses, and Random Forest analyses. Our under-standing of molecular features or properties associated withcertain pharmacological end points has also dramaticallyincreased. For example, it has been widely recognized thatcertain structural features can be associated with toxicity,while other molecular properties (such as ClogP, molecularweight, and polar surface area) can be associated with oralbioavailability

1,3-DIARYL-2-CARBOXYINDOLES AS POTENT NON-PEPTIDE ENDOTHELIN ANTAGONISTS

Abstract Endothelin-1 is a potent vasoconstrictor that is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists including PD 159110 ( 31 ), an ET A selective antagonist, and PD 159020 ( 37 ), a non-selective ET A /ET B antagonist. The discovery, synthesis, and structure-activity relationships of this series of compounds are described.

An efficient synthesis of 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2,2-methylpropyl)carbamoyl)benzoic acid: a factor VIIa inhibitor discovered by the Ono Pharmaceutical Company

Abstract A small molecule factor VIIa inhibitor has recently been reported by the Ono Pharmaceutical Company. Herein, we outline an efficient and convergent, synthetic route that relies upon a palladium-catalyzed Stille coupling reaction as a key step for the synthesis of the inhibitor.

Progress in the discovery of Factor Xa inhibitors

Factor Xa is a serine protease that has a critical role in the blood coagulation cascade by ultimately regulating the production of thrombin. There is now ample evidence for the role of Factor Xa inhibitors as anticoagulants and they represent potential new therapeutic agents for the treatment and prevention of arterial and venous thrombosis. During the past five years, research in the field of Factor Xa inhibitors has been marked with enormous efforts to identify highly potent, selective and orally-active agents. This research has led to the discovery of a number of clinical candidates that are currently progressing at different stages of drug development. This review examines the patent and scientific literature during the period 2000 – 2005.

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications.

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.

Chapter 6. Thrombin and Factor Xa Inhibition

Publisher Summary This chapter discusses the recent studies on experimental and clinical pharmacology of thrombin and factor Xa inhibitors. Several recent studies have utilized defined biochemical systems, particularly plasma, to characterize the mechanism of action profiles for a variety of anti-thrombin agents. Following the promising anti-thrombotic efficacy, afforded by the direct thrombin inhibitors hirudin and hirulog, recent attention has focused on the design of low molecular weight thrombin active site inhibitors. These inhibitors address the limitations of previous anti-thrombotics, including bleeding propensity, serine protease selectivity, lack of significant oral bioavailability, and inability to inhibit clot-bound thrombin. An alternative anti-thrombotic strategy has also emerged in the form of inhibitors of factor Xa, the penultimate serine protease in the blood coagulation cascade. The factor Xa inhibitors known to date can be classified into three types— namely, endogenous inhibitors that are present in the blood including anti-thrombin III (ATIII) and tissue factor pathway inhibitor (TFPI), inhibitors isolated from the salivary glands of blood sucking insects and animals, and rational drug designed inhibitors comprising of peptides and nonpeptides. This enzyme, as a part of a prothrombinase complex composed of nonenzymatic co-factor Va, calcium ions, and a phospholipid membrane surface regulates the generation of thrombin from its zymogen prothrombin. Polypeptide factor Xa inhibitors have demonstrated that specific inhibition of factor Xa is a valid anti-thrombotic strategy, and hence low molecular weight agents that selectively inhibit factor Xa or clot-bound factor Xa are currently being developed. Factor Xa inhibitors offer the attractive potential to suppress thrombin generation, while, as competitive inhibitors, allowing some platelet aggregation. This translates to a reduced bleeding tendency and presents an exciting area for drug development.

Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors.

Bicyclic piperazinone based thrombin inhibitors of general structure 2 were prepared and evaluated in vitro and in vivo. These inhibitors, having in common an electrophilic basic trans-cyclohexylamine P1 residue, displayed high thrombin affinity, high selectivity against trypsin and good in vivo efficacy in the rat arterial thrombosis model.

Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications.

Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.

Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through P1 residues.

Peptidomimetic inhibitors of thrombin lacking the important Ser195-carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.

Novel bicyclic lactam inhibitors of thrombin: Highly potent and selective inhibitors

The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.