Christopher A. Lipinski

Lead- and drug-like compounds: the rule-of-five revolution.

Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochemical features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clinical success. Physicochemical features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compounds differ from those of drug-like compounds is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chemical tools to probe biology space. All these topics frame the scope of this short review/perspective.:

Navigating chemical space for biology and medicine

Despite over a century of applying organic synthesis to the search for drugs, we are still far from even a cursory examination of the vast number of possible small molecules that could be created. Indeed, a thorough examination of all ‘chemical space’ is practically impossible. Given this, what are the best strategies for identifying small molecules that modulate biological targets? And how might such strategies differ, depending on whether the primary goal is to understand biological systems or to develop potential drugs?

Increased Fibroblast Growth Factor-Inducible 14 Expression Levels Promote Glioma Cell Invasion via Rac1 and Nuclear Factor-κB and Correlate with Poor Patient Outcome

Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion throughout the central nervous system. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of Rac1 by small interfering RNA inhibits this cellular response. Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-kappaB (NF-kappaB) activity. The Fn14 promoter region contains NF-kappaB binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade and inversely correlate with patient survival. These results show that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Such a feedback loop argues for aggressive targeting of the Fn14 axis as a unique and specific driver of glioma malignant behavior.

A crowdsourcing evaluation of the NIH chemical probes.

Between 2004 and 2008, the US National Institutes of Health Molecular Libraries and Imaging initiative pilot phase funded 10 high-throughput screening centers, resulting in the deposition of 691 assays into PubChem and the nomination of 64 chemical probes. We crowdsourced the Molecular Libraries and Imaging initiative output to 11 experts, who expressed medium or high levels of confidence in 48 of these 64 probes.

Chapter 27. Bioisosterism in Drug Design

Publisher Summary This chapter reviews progress in the use of bioisosterism in drug design. The broadest definition of bioisosteres is, “groups or molecules those have chemical and physical similarities producing broadly similar biological properties”. A major trend in this area is the increasing prevalence of “nonclassical isosteres” moieties those do not have the same number of atoms, but produce a similarity in a key parameter. Similar effects in two functional groups does not imply atom upon atom overlap. Bioisosterism is part of the spectrum of QSAR. In theory, bioisosterism lends itself to computer substructure searching especially as a means of developing new leads or new series. In practice, examples of new lead generation using bioisosteric principles are few. The chapter describes peptide and dipeptide bioisosteres, amide carbonyl group bioisosteres, ketone carbonyl bioisosteres, ester carbonyl bioisosteres, ester ether oxygen bioisosteres, phosphate bioisosteres, catechol bioisosteres, urea, thiourea bioisosteres, carboxylic acid bioisosteres, ring equivalents, and some basic groups. Bioisosteric substitution of the ammonium group by a sulfonium group finds application in studies on dopamine agonists such as and the isolevorphanol opiate analog . The bioisosteric relationship between aminoalkyl, 2-imidazolidine and 4-imidazole moieties in histamine H 1 receptor antagonists and the similarity between amidines and 2-amino pyridines led to bioisosteric design of the histamine H 2 -receptor antagonist.

Targeting Pyk2 for therapeutic intervention

Importance of the field: The focal adhesion tyrosine kinases FAK and Pyk2 are uniquely situated to act as critical mediators for the activation of signaling pathways that regulate cell migration, proliferation and survival. By coordinating adhesion and cytoskeletal dynamics with survival and growth signaling, FAK and Pyk2 represent molecular therapeutic targets in cancer as malignant cells often exhibit defects in these processes. Areas covered in this review: This review examines the structure and function of the focal adhesion kinase Pyk2 and intends to provide a rationale for the employment of modulating strategies that include both catalytic and extra-catalytic approaches that have been developed in the last 3 – 5 years. What the reader will gain: Targeting tyrosine kinases in oncology has focused on the ATP binding pocket as means to inhibit catalytic activity and downregulate pathways involved in tumor invasion. This review discusses the available catalytic inhibitors and compares them to the alternative approach of targeting protein–protein interactions that regulate kinase activity. Take home message: Development of specific catalytic inhibitors of the focal adhesion kinases has improved but significant challenges remain. Thus, approaches that inhibit the effector function of Pyk2 by targeting regulatory modules can increase specificity and will be a welcome asset to the therapeutic arena.

Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824

Nitroimidazoles such as PA-824 and OPC-67683 are currently in clinical development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compounds is high, they both suffer from poor water solubility thus complicating development. We determined the single crystal X-ray structure of PA-824 and found a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. To attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, we prepared the two diastereomers of the 7-methyl-nitroimidazo-oxazine. Determination of the crystal structure of the 7-(S)-methyl derivative (5, cis) revealed that the benzylic side chain remained pseudoaxial while the 7-(R)-methyl derivative (6, trans) adopted the desired pseudoequatorial conformation. Both derivatives displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aqueous solubility, suggesting that inherent lattice stability is not likely to be a major factor in limiting solubility. Conformational analysis revealed that all three compounds have similar energetically accessible conformations in solution. Additionally, these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position.

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier.

Chapter 17. Aldose Reductase Inhibitors as a New Approach to the Treatment of Diabetic Complications

Publisher Summary Several excellent reviews of the recent advances in the understanding of the biochemical events contributing to the pathophysiology of diabetic complications have focused upon aldose reductase (AR) inhibitors. The biological rationale and chemical progress toward design of AR inhibitors constitute the major discussion of this chapter. Diabetes mellitus (DM) that consists of an absolute (Type I or insulin dependent, IDDM) or relative (Type II or non-insulin-dependent, NIDDM) lack of insulin is a disease of increasing incidence. Diabetics also have a three or four times greater chance of developing peripheral arterial disease and a five times greater chance than the general population of developing gangrenes that leads to amputation. Recently, theories and data have been emerging that implicate aldose reductase (AR), increased flux through the polyol pathway due to hyperglycemia, and accumulation of sorbitol and fructose in the pathophysiology of diabetic complications. Because of the high Km of AR for glucose, it is hypothesized that under normoglycemic conditions there is very little flux through the polyol pathway. On the other hand, under conditions of hyperglycemia, as in diabetes, the flux through this pathway can be considerable and the products of the pathway, sorbitol and fructose, are slowly metabolized and not freely diffusible through the cell plasma membrane, and thus tend to accumulate in the tissues. The chapter in its early phase discusses the extensive biological data based on this agent as a probe for the role of AR inhibition in the treatment of diabetic complications. Significant differences in susceptibility of AR enzymes to inhibition have been observed by the researchers. No trends can be predicted other than that in general human placental AR (HPAR) is less susceptible to inhibition than other AR enzymes.

Bioisosteric design of conformationally restricted pyridyltriazole histamine H2-receptor antagonists

A process of bioisosteric drug design is described whereby, in a manner analogous to synthesis, key portions of an effector molecule are successively replaced by pharmacophores or bioisosteres. This process, when applied to histamine, leads to the competitive histamine H2-receptor antagonist prototype 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (7). The biaryl nature of 7 fixes internitrogen distances, and comparison of these with histamine suggests that 7 shares structural features more in common with histamine trans rather than histamine gauche conformations. Alkylation of the prototype pyridylamino group in 7 markedly improves both histamine H2-receptor antagonist and gastric acid antisecretory activity so that the resulting agent, 3-amino-5-[2-(ethylamino)-4-pyridyl]-1,2,4-triazole (8), is more active than cimetidine.