Robert Alan Goodnow

Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: preclinical and clinical developments

Leukotriene B4 (LTB4) is a lipid inflammatory mediator derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2 (PLA2), 5-lipoxygenase (5-LO) and leukotriene A4 (LTA4) hydrolase. Several inflammatory diseases, including asthma, chronic obstructive pulmonary disease, arthritis and inflammatory bowel disease, have been associated with elevated levels of LTB4. As a result, pharmacological strategies to modulate the synthesis of LTB4 (inhibition of PLA2, 5-LO or LTA4 hydrolase) or the effects of LTB4 itself (antagonism of LTB4 receptors) are being developed by several companies. Two G-protein-coupled receptors mediate the effects of LTB4, namely BLT1 and BLT2. The pharmacology, expression and function of these two receptors were last reviewed by Tager and Luster in 2004. Since then, there has been an increased understanding of the function of these receptors, in particular for the lesser understood of the two receptors, BLT2. Furthermore, since last reviewed in 1996, there have been several clinical developments in the use of BLT receptor antagonists for inflammatory diseases. This review summarizes the latest preclinical and clinical developments in BLT antagonism for inflammatory diseases and discusses potential future developments.

DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries

Complex mixtures of DNA encoded small molecules may be readily interrogated via high-throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules that interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small molecule moieties of DELs are generally synthesized though a multistep process, and each chemical step is accomplished while it is simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein, protocols for 24 reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multistep synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reactions including BOC deprotection (under pH neutral conditions), carbamylation, and Sonogashira coupling. Last, step-by-step protocols for synthesizing functionalized DELs from trichloronitropyrimidine and trichloropyrimidine scaffolds are detailed.

Current practices in generation of small molecule new leads

The current drug discovery processes in many pharmaceutical companies require large and growing collections of high quality lead structures for use in high throughput screening assays. Collections of small molecules with diverse structures and “drug‐like” properties have, in the past, been acquired by several means: by archive of previous internal lead optimization efforts, by purchase from compound vendors, and by union of separate collections following company mergers. More recently, many drug discovery companies have established dedicated efforts to effect synthesis by internal and/or outsourcing efforts of targeted compound libraries for new lead generation. Although high throughput/combinatorial chemistry is an important component in the process of new lead generation, the selection of library designs for synthesis and the subsequent design of library members has evolved to a new level of challenge and importance. The potential benefits of screening multiple small molecule compound library designs against multiple biological targets offers substantial opportunity to discover new lead structures. Subsequent optimization of such compounds is often accelerated because of the structure‐activity relationship (SAR) information encoded in these lead generation libraries. Lead optimization is often facilitated due to the ready applicability of high‐throughput chemistry (HTC) methods for follow‐up synthesis. Some of the strategies, trends, and critical issues central to the success of lead generation processes are discussed below. J. Cell. Biochem. Suppl. 37: 13–21, 2001.

Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates

Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma.

Hit and lead identification : Efficient practices for drug discovery

Publisher Summary The identification of high-quality leads has become an important part of the process of drug discovery. The process of lead identification has been formalized to a greater or lesser extent in different companies, and publications have started to appear describing the various strategies that have been implemented. However, the practice in the medicinal chemistry literature still reflects the historical focus on potency. It has been pointed out that the historical focus on potency in the early stages of drug discovery has given way to a more balanced process, where additional factors, such as physicochemical properties, pharmacokinetics, and even safety, are addressed before significant resources are committed to a chemical series.

Lead generation: reality check on commonly held views

Background: Lead generation is a critical element in the successful discovery of new drugs. Scientists engaged in lead generation are faced with a huge array of strategies and technologies, and new approaches are constantly emerging. In part as a reaction to the large number of options, several guidelines have been developed over the last 10 – 20 years that enable scientists to focus on approaches which are likely to lead to the discovery and development of orally available drugs. Objective and conclusions: This paper examines some of these guidelines as they relate to specific examples of lead generation for drug discovery, and contends that in many cases valuable discoveries can be made at the margins or even outside areas considered mainstream.

Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.

The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

Efficient Synthesis of Aryl Methyl Sulfide Derivatives Using (Methylthio)trimethylsilane as Methylthiolation Reagent

The synthesis of various aryl methyl sulfides has been achieved by treatment of nitroarenes with a combination of (methylthio)trimethylsilane and cesium carbonate in dimethylsulfoxide. This reaction gives access to aryl methyl sulfide derivatives in high yields.

A new polymer-bound N-hydroxysuccinimidyl active ester linker

Abstract Synthesis of a new N -hydroxysuccinimidyl resin is described and the N -acylation with this resin provides amide products in high yields and excellent purities. This new linker is suitable for combinatorial library synthesis.

Practical synthesis of 5-aryl-3-alkylsulfonyl-phenol and 5-aryl-3-arylsulfonyl-phenol libraries.

A straightforward and cost-effective synthesis of 5-aryl-3-alkylsulfonyl-phenols by a sequential scaffold derivatization strategy has been developed. The procedure is suitable for parallel synthesis of small libraries around the biphenyl privileged core having an unusual 1,3,5-substitution pattern. The synthesis is exemplified by a pilot library of 30 compounds.