Hydantoin based inhibitors of MMP13—Discovery of AZD6605

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.     

Medicinal chemistry and therapeutic potential of CpG DNA

The observation that oligodeoxynucleotides containing CpG dinucleotides (CpG DNA) exhibit several immunological effects has led to their use as therapeutic agents and adjuvants for various diseases. Several CpG DNA drug candidates are currently being evaluated, either as monotherapies or as adjuvants (with vaccines, antibodies, antigens and allergens), in preclinical and clinical trials against cancers, viral and bacterial infections, allergies and asthma. Knowledge gained from studies of the medicinal chemistry of CpG DNA has provided a basis for designing a second generation of CpG DNA agents with desirable cytokine-inducing and potent immunomodulatory activity. This article reviews recent progress in understanding the effects of CpG DNA, the medicinal chemistry of CpG DNA, and its possible therapeutic applications.     

氟化天然产物生物合成的研究进展

氟元素是一种具有特殊性质的卤素,含氟有机物可广泛应用于生物有机化学、药物化学和生物材料科学等领域.尽管C-F键的合成方法有所创新,但将氟元素掺入到结构复杂的生物活性分子中的方法较少,因此选择性的氟化仍极具挑战性.本文从自然界中氟化天然产物及氟化酶的发现、氟化天然产物的合成通路、氟化天然产物合成机制的意义、氟化酶的进化及...     

The potential of organometallic complexes in medicinal chemistry

Organometallic complexes have unique physico-chemical properties, which have been widely used in homogenous catalysis, for example, for the synthesis of lead compounds and drug candidates. Over the past two decades, a few scientists from all over the world have extended the use of the specific characteristics of these compounds (e.g. structural diversity, possibility of ligand exchange, redox and catalytic properties) for medicinal purposes. The results are stunning. A few organometallic compounds have already entered clinical trials and it can be anticipated that several more will follow in coming years. In this short review, we present the specific advantages that organometallic metal complexes have over purely organic and also coordination compounds. Furthermore, using specific examples, we illustrate how these particular properties can be put to good use in medicinal chemistry. The examples we present have an emphasis on, but are not restricted to, anti-cancer activity.     

Therapeutic peptides: technological advances driving peptides into development

As potential therapeutics, peptides offer several advantages over small molecules (increased specificity) and antibodies (small size). Nevertheless, a number of key issues have hampered their use as drug candidates. A series of new technologies have recently been developed that allow peptides to be viable drug candidates in areas usually restricted to protein therapeutics, such as monoclonal antibodies. These include the development of various types of peptide-conjugates that have lower rates of clearance and hence the potential to increase the exposure of peptide drug candidates in chronic diseases. Structural additions have also been made to peptides, including the use of unnatural amino acids, mainchain modifications and other novel substitutions, which have helped to improve peptide stability and further their therapeutic potential.     

Advances in the synthesis and recent therapeutic applications of 1,2,4-thiadiazole heterocycles

Chemical properties of 1,2,4-thiadiazole have been reviewed in the last few years. However, the usefulness of 1,2,4-thiadiazole as a privileged system in medicinal chemistry has prompted the advances on the therapeutic potential of this system. This review provides a brief summary of the medicinal chemistry of 1,2,4-thiadiazole system and highlights some examples of 1,2,4-thiadiazole-containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 1,2,4-thiadiazole is presented in sections by generalized synthetic methods.     

Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.     

Antisense technology.

During the past 12 months, significant advances have been reported in the medicinal chemistry, and the pharmacodynamic and pharmacokinetic characterization of oligonucleotides. Advances in medicinal chemistry suggest that the scope for additional modifications as a means of developing therapeutic agents is substantial. This is confirmed by our clearer understanding of the pharmacodynamic and pharmacokinetic properties of oligonucleotides and the increasing number of molecular targets against which they have been shown to be active.     

Improving success rates for lead generation using affinity binding technologies

Affinity technologies have been applied at several stages of the drug discovery process, ranging from target identification and purification to the identification of preclinical candidates. The detection of ligand-macromolecule interactions in lead discovery is the best studied and most powerful of these techniques. Although affinity methods have been in widespread use for about a decade, only recently have many reports emerged on their utility. Primary affinity screens of large libraries of small molecules or fragments have begun to produce results for challenging targets. Furthermore, in secondary assays affinity methods are opening new avenues to tackle important medicinal chemistry tasks.     

Sulfonamide derivatives as multi-target agents for complex diseases

Sulfonamide derivatives are frequently seen structural motifs in medicinal chemistry. Almost a century after Gerhard Domagk’s pioneering work leading to the first sulfonamide antibiotic Prontosil, sulfa-drugs are still widely utilized in various pharmaceutical applications due to their antibacterial, antiviral, antimalarial, antifungal, anticancer, antidepressant, or other properties. In the past few years, the interest in sulfonamides has increased as their broad range of bioactivity and versatile structure make them excellent candidates for repurposing old drugs or developing new multi-target agents in the emerging field of polypharmacology.This digest aims to provide an overview of recent advances in sulfonamide-based bioactive compounds, their importance in drug discovery and development emphasizing multi-target approaches for complex diseases, and their novel contribution to contemporary medicinal chemistry.     

Polymersomes: a new multi-functional tool for cancer diagnosis and therapy

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties. The polymersome architecture, with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane, provides significant storage capacity for both water soluble and insoluble substances (such as drugs and imaging probes). Further, the brush-like architecture of the polymersome outer shell can potentially increase biocompatibility and blood circulation times. A further recent advance is the development of multi-functional polymersomes that carry pharmaceuticals and imaging agents simultaneously. The ability to conjugate biologically active ligands to the brush surface provides a further means for targeted therapy and imaging. Hence, polymersomes hold enormous potential as nanostructured biomaterials for future in vivo drug delivery and diagnostic imaging applications.     

Fluorine biocatalysis

The introduction of fluorine atoms into organic molecules has received considerable attention as these organofluorines have often found widespread applications in bioorganic chemistry, medicinal chemistry and biomaterial science. Despite innovation of synthetic C–F forming methodologies, selective fluorination is still extremely challenging. Therefore, a biotransformation approach using fluorine biocatalysts is needed to selectively introduce fluorine into structurally diverse molecules. Yet, there are few ways that enable incorporation of fluorine into structurally complex bioactive molecules. One is to extend the substrate scope of the existing enzyme inventory. Another is to expand the biosynthetic pathways to accept fluorinated precursors for producing fluorinated bioactive molecules. Finally, an understanding of the physiological roles of fluorometabolites in the producing microorganisms will advance our ability to engineer a microorganism to produce novel fluorinated commodities. Here, we review the fluorinase biotechnology and fluorine biocatalysts that incorporate fluorine motifs to generate fluorinated molecules, and highlight areas for future developments.     

The successful quest for oral factor Xa inhibitors; learnings for all of medicinal chemistry?

The medicinal chemistry of oral small molecule factor Xa inhibitors is discussed, highlighting key advances that led to clinical candidates and the first licensed medicines. Identification of neutral ligands for the primary specificity pocket was a key discovery; capitalised upon by structure based design and combinatorial methods to deliver many variations on the theme; but it was good medicinal chemistry practice, in the optimisation of physical properties, which ultimately delivered efficacious compounds with adequate oral exposure. As a retrospective appraisal, representative compounds were profiled using the more contemporary concepts of Ligand Efficiency and Property Forecast Indices; which gave clear indications of the value of these principles.     

Chalcone derivatives and their antibacterial activities: Current development

The increase in antibiotic resistance due to various factors has encouraged the look for novel compounds which are active against multidrug-resistant pathogens. In this framework, chalcone-based compounds showed a diversity of pharmacological properties, and its derivatives possess a high degree of structural diversity, and it is helpful for the discovery of new therapeutic agents. The growing resistance to antibiotics worldwide has endangered their efficacy. This has led to a surging interest in the discovery of new antibacterial agents. Thus, there is an urgent need for new antibacterial drug candidates with increased strength, new targets, low cost, superior pharmacokinetic properties, and minimum side effects. The present review concluded and focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potent antibacterial agents and also describes its structure-activity relationships studies. The various synthetic structures leading to this class of neutral protective compound is common and additional structural optimization is promising for potential drug discovery and development.     

Small molecule microarrays: recent advances and applications

Directed or exploratory drug development programs constantly seek robust screening platforms for the high fidelity identification and validation of potential targets. Small-molecule microarrays (SMMs) have risen to this call by elegantly forging the capability of combinatorial chemistry in producing myriad compounds with the powerful throughput afforded by microarrays. This synergism offers scientists a versatile tool for rapid compound analysis and discovery. Microarrays of small molecules have already been successfully applied in important areas ranging from protein profiling to the discovery of therapeutic leads. Recent interesting developments towards improved immobilization strategies and library creation methods, together with novel advances herein described, have set the stage for SMMs to take on wider and more routine applications in academia and industry. As a rapidly maturing technology, SMMs pave the way forward in high-throughput exploration, both in the identification of biologically significant natural and synthetic small molecules and in harnessing their vast potential towards medicinal and diagnostic applications.     

Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors

Bioisosteres are integral components of modern pharmaceutical research that allow structural optimization to maximize in vivo efficacy and minimize adverse effects by selectively modifying pharmacodynamic, pharmacokinetic and physicochemical properties. A recent medicinal chemistry campaign focused on identifying small molecule inhibitors of prolylcarboxypeptidase (PrCP) initiated an investigation into the use of pyrazoles as bioisosteres for amides. The results indicate that pyrazoles are suitable bioisosteric replacements of amide functional groups. The study is an example of managing bioisosteric replacement by incorporating subsequent structural modifications to maintain potency against the selected target. A heuristic model for an embedded pharmacophore is also described.     

Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists

A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.     

Adapting protein sequences for optimized therapeutic efficacy

Therapeutic proteins alleviate disease pathology by supplementing missing or defective native proteins, sequestering superfluous proteins, or by acting through designed non-natural mechanisms. Although therapeutic proteins often have the same amino acid sequence as their native counterpart, their maturation paths from expression to the site of physiological activity are inherently different, and optimizing protein sequences for properties that 100s of millions of years of evolution did not need to address presents an opportunity to develop better biological treatments. Because therapeutic proteins are inherently non-natural entities, optimization for their desired function should be considered analogous to that of small molecule drug candidates, which are optimized through expansive combinatorial variation by the medicinal chemist. Here, we review recent successes and challenges of protein engineering for optimized therapeutic efficacy.     

A database for medicinal and aromatic plants of JK (Jammu and Kashmir) in India

High throughput screening of small molecules for a given drug target is achieved using plant materials of medicinal value. Therefore, it is important to document the availability and location of such medicinal plants in the form of a database. Here, we describe a web database containing information (botanical name, common name, local name, botany, chemistry, folklore medicinal use and medicinal uses) about the medicinal and aromatic plants available in JK (Jammu and Kashmir). The database is available for free in public domain.

Availability     

Targeted quantum dot conjugates for siRNA delivery

Treatment of human diseases such as cancer generally involves the sequential use of diagnostic tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging functions in a single vehicle promise to change this paradigm. in particular, nanoparticle-based multifunctional platforms offer the potential to improve the pharmacokinetics of drug formulations, while providing attachment sites for diagnostic imaging and disease targeting features. We have applied these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered by rapid excretion and nontargeted tissue distribution. Using a PEGlyated quantum dot (QD) core as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle's surface. We found that the homing peptide was required for targeted internalization by tumor cells, and that siRNA cargo could be coattached without affecting the function of the peptide. Using an EGFP model system, the role of conjugation chemistry was investigated, with siRNA attached to the particle by disulfide cross-linkers showing greater silencing efficiency than when attached by a nonreducible thioether linkage. Since each particle contains a limited number of attachment sites, we further explored the tradeoff between number of F3 peptides and the number of siRNA per particle, leading to an optimized formulation. Delivery of these F3/siRNA-QDs to EGFP-transfected HeLa cells and release from their endosomal entrapment led to significant knockdown of EGFP signal. By designing the siRNA sequence against a therapeutic target (e.g., oncogene) instead of EGFP, this technology may be ultimately adapted to simultaneously treat and image metastatic cancer.