Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

In peripheral sensory neurons, the vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) functions as a molecular integrator of painful stimuli, including those mediated by capsaicin, acid, and heat. Antagonist blockade of TRPV1 activation is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. TRPV1 is also expressed, albeit at lower levels, in the brain and in non‐neuronal tissues, where its function(s) remains elusive. The contribution of TRPV1 receptor activity to physiological reflexes and disease states is complex and is only beginning to be understood. Consequently, the resultant effects of TRPV1 antagonists on the body may be unforeseen. Indeed, clinical trials with a number of TRPV1 antagonists were recently terminated due to their marked hyperthermic activity. In this review article, the medicinal chemistry of TRPV1 antagonists is discussed inasmuch as it relates to the efficacy, safety, tolerability and potential side effects of these compounds. In addition, the available information on the current status of the clinical trials with TRPV1 antagonists is summarized. Drug Dev Res 68:477–497, 2007. © 2008 Wiley‐Liss, Inc.     

Medicinal chemistry of sirtuin inhibitors

As members of Class III histone deacetylases (HDACs), sirtuins use stoichiometric nicotinamide adenine dinucleotide (NAD(+)) to remove the acetyl group from N-acetyl-lysines of histones or non-histone proteins. Sirtuins have been implicated in metabolic diseases, cancer, and neurodegenerative diseases, constituting a promising target for drug discovery. While the early sirtuin inhibitors mimicked NAD(+) or substrate peptides, high-throughput and in silico screenings have identified a wide range of core structures, many of which have been subjected to medicinal chemistry efforts. This review outlines inhibitor chemotypes, and their chemical modifications and biological evaluations, highlighting strategies to enhance inhibitory activity and selectivity among isoforms.     

Medicinal chemistry and the pharmacy curriculum

The origins and advancements of pharmacy, medicinal chemistry, and drug discovery are interwoven in nature. Medicinal chemistry provides pharmacy students with a thorough understanding of drug mechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A comprehensive understanding of the chemical basis of drug action equips pharmacy students with the ability to answer rationally the "why" and "how" questions related to drug action and it sets the pharmacist apart as the chemical expert among health care professionals. By imparting an exclusive knowledge base, medicinal chemistry plays a vital role in providing critical thinking and evidence-based problem-solving skills to pharmacy students, enabling them to make optimal patient-specific therapeutic decisions. This review highlights the parallel nature of the history of pharmacy and medicinal chemistry, as well as the key elements of medicinal chemistry and drug discovery that make it an indispensable component of the pharmacy curriculum.     

Medicinal chemistry and properties of 1,2,4-thiadiazoles

1,2,4-Thiadiazole is a distinctive class of small heterocyclic thiol trapping agents that serve as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins. X-Ray crystal structures of enzyme-inhibitor complex indicate that the cysteine thiol reacts with the N-S bond of the thiadiazole moiety to form a disulfide bond resulting in the inactivation of the enzymes. This review addresses the medicinal chemistry and various properties of 1,2,4-thiadiazoles in their potential as new electrophilic "warheads" for targeting the cysteine residues of biomolecules (e.g, H+/K+ ATPase), and cysteine-dependent enzymes (e.g., cathepsin B and transglutaminase).     

Medicinal chemistry awards symposium.

Although of perhaps limited interest to scavengers of hard biological information, one of the undoubted highlights of the third day of the conference was the Medicinal Chemistry Awards Symposium. Two venerable chemists gave resumés of their life's work, and updated the audience on their current research. This was followed by a new award for team innovation.     

Medicinal chemistry of Hsp90 inhibitors

Heat shock protein (Hsp90) inhibitors are an increasingly interesting and important class of compounds where the first in class, natural product derived inhibitors such as 17-allylaminogeldanamycin (17-AAG), are entering late stage clinical development. Recently the emergence of synthetic, small molecule inhibitors has been described and both NVP-AUY922 and BIIB021 have entered clinical development. The medicinal chemistry of these and other published small molecule Hsp90 inhibitors is described in this review.     

Medicinal chemistry of target family-directed masterkeys

The majority of pharmaceutically relevant drug targets cluster into densely populated target families, thus offering a novel approach that complements the currently favoured screening paradigm in medicinal chemistry. This approach uses a privileged structure concept whereby molecular masterkeys are developed that account for a target family wide structural or functional commonality. Numerous lead compounds, based on multipurpose privileged structures, can be generated that address a variety of targets from a gene family of interest, irrespective of therapeutic area. Several different interpretations of the privileged structure concept will be highlighted, with a strong emphasis on the most stringent application: the optimization of a molecular masterkey for a distinct target family of interest.     

Abstracts of papers Medicinal chemistry meeting

Ch. J. van Koppen is a recipient of an American Heart Association, Washington Affiliate postdocoral fellowship.     

Anticancer activity of artemisinin-derived trioxanes

The recent scientific and patent literature on therapeutically promising anticancer trioxanes derived from the antimalarial artemisinin are reviewed through mid-2006. Several of these new chemical entities, especially some trioxane dimers, have selective and very potent anticancer activity even at low nanomolar concentrations. A major opportunity exists for the development of these and related trioxanes into anticancer drug candidates.     

Medicinal chemistry insights into antiviral peptidomimetics

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Medicinal chemistry poster sessions I.

There were two extensive medicinal chemistry poster sessions, which provided information on a huge range of novel compounds. The first of the two sessions was preceded by the Divisional Business Meeting, which was presided over by C McLelland.     

Medicinal chemistry targeting nucleosides and nucleic acids based on fine synthetic chemistry

Nucleosides and nucleotides are one of the most important elements for cells by the fact that they are components of DNAs and RNAs. In addition, they play important roles in most fundamental cellular metabolic pathways such as energy donors, second messengers, and cofactors for various enzymes. Therefore, there exists a rich source in drug discovery targeting nucleosides and nucleotides. In order to utilize nucleosides and nucleic acids on the drug development, it is very important to develop reactions and methods, by which the highly coordinating and labile nucleoside intermediates can be used. With these in mind, we have been working on synthetic nucleoside and nucleic acid chemistry. First, branched sugar nucleoside derivatives, which are potential antitumor agents, have been synthesized utilizing samarium diiodide (SmI(2)) mediated Reformatsky reaction or aldol reaction. 3'-beta-Carbamoylmethylcytidine (CAMC) was found to exhibit potent cytotoxicity against various human tumor cell lines. Synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including beta-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs. Medicinal chemistry of oligodeoxynucleotides has been conducted. Thus, novel triazole-linked dumbbell oligodeoxynucleotides and modular bent oligodeoxynucleotides were synthesized. They exhibit excellent binding affinity to NF-kappaB or HMGB1 A-box protein, which are important therapeutic targets. Therefore, the results obtained conclusively demonstrated these oligodeoxynucleotides could be proposed as powerful decoy molecules.     

Medicinal chemistry of selective neurokinin-1 antagonists

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interaction of the neuropeptide substance P with it's G-protein coupled receptor, will provide improvements over existing therapies. For this reason many pharmaceutical companies are engaged in intense research programs with the goal of bringing safe and effective new drugs to the market. To date a wealth of diverse NK1 antagonists have been discovered, several of which have been evaluated in clinical trials. Despite rich structural diversity in this area of medicinal chemistry a number of structural features are commonly shared amongst otherwise unrelated antagonists. This theme and others are covered with the aim of conveying recent successful approaches to the discovery of potent and selective nonpeptide NK1 antagonists. This review focuses mainly on reports appearing in the year 2001 and the first half of 2002.