Medicinal Chemistry Strategies Research Articles

Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors.

Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which have the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics of CKIs and discovery of additional irreversible and reversible-covalent cysteine-targeted warheads has inspired the development of this area. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative CKIs, which are categorized by the location of the target cysteine within seven main regions of the kinase: the front region, the glycine rich loop (P-loop), the hinge region, the DFG region, the activation loop (A-loop), the catalytic loop (C-loop), and the remote loop. The emphasis is placed on the design and optimization strategies of CKIs that are generated by addition of a warhead to a reversible lead/inhibitor scaffold. In addition, we address the challenges facing this area of drug discovery.

Medicinal Chemistry Strategies Towards SO2 Donors as Research Tools and Potential Therapeutics.

SO2 is emerging as a possible endogenous signaling molecule in mammals. In addition, SO2 has also shown pharmacological effects, presenting SO2 as a promising potential therapeutic agent. The past decade has witnessed steady advances in the development of small molecule-based SO2 prodrugs/donors with varied release mechanisms. Herein, we summarize various strategies employed for SO2 prodrug design. The remaining challenges and issues will also be discussed.

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and PROTAC-based degraders for cancer therapy

Indoleamine 2,3-dioxygenase 1 (IDO1), a known immunosuppressive enzyme that catalyzes the rate-limiting step in the oxidation of tryptophan (Trp) to kynurenine (Kyn), has received increasing attention as an attractive immunotherapeutic target for cancer therapy. Up to now, eleven small-molecule IDO1 inhibitors have entered clinical trials for the treatment of cancers. In addition, proteolysis targeting chimera (PROTAC) based degraders also provide prospects for cancer therapy. Herein we present a comprehensive overview of the medicinal chemistry strategies and potential therapeutic applications of IDO1 inhibitors in nonclinical trials and IDO1-PROTAC degraders.

Visible-light-promoted late-stage direct fluoroalkylation of nitroimidazoles

Incorporation of fluoroalkyl groups into bioactive compounds can dramatically change their physicochemical and physiological properties, and further improve their pharmacokinetic as well as pharmacological profiles. Therefore, the fluoroalkylation has been acknowledged as a vital strategy in medicinal chemistry for drug discovery. In this study, an efficient and convenient method for the preparation of fluoroalkylated nitroimidazoles through visible-light-prompted direct radical reaction with commercially available materials is described. The strategy proceeds smoothly under mild conditions to afford the fluoroalkyl nitroimidazoles under mild conditions. In addition, control experiments have been performed, revealing a radical process involved in the reaction mechanism. Preliminary evaluations on some products display enhanced antibacterial activities, which further demonstrates the approach to be a versatile protocol for the late-stage fluoroalkylation of clinical drugs toward a diversity-oriented drug discovery.

Novel Strategies in C-H Oxidations for Natural Product Diversification-A Remote Functionalization Application Summary.

Selectively activating the distal inactive C-H bond for functionalization is one of the on-going challenge in organic synthetic chemistry. In recent years, benefiting from the development of selective synthesis methods, novel methodologies not only make it possible to break non-traditional chemical bonds and attain more diversity in inactive sites, but also provide more possibilities for the diversification of complex natural products. Direct C-H bond functionalization approaches make it feasible to explore structure-activity relationship (SAR), generate metabolites and derivatives, and prepare biological probes. Among them, direct oxidation of inert C-H bonds is one of the most common methods for natural product diversification. In this review, we focus on the application of remote functionalization of inert C-H bonds for natural products derivatization, including the establishment of oxidation methods, the regulation of reaction sites, and the biological activities of derivatives. We highlight the challenges and opportunities of remote functionalization of inert C-H bonds for natural product diversification through selected and representative examples. We try to show that inert C-H bond oxidation, properly regulated and optimized, can be a powerful and efficient strategy in both synthetic and medicinal chemistry.

Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors.

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7

The atypical chemokine receptor C–X–C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure–activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Peptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases.

ADAM and ADAMTS are two large metalloproteinase families involved in numerous physiological processes, such as shedding of cell-surface protein ectodomains and extra-cellular matrix remodelling. Aberrant expression or dysregulation of ADAMs and ADAMTSs activity has been linked to several pathologies including cancer, inflammatory, neurodegenerative and cardiovascular diseases. Inhibition of ADAM and ADAMTS metalloproteinases have been attempted using various small molecules and protein-based therapeutics, each with their advantages and disadvantages. While most of these molecular formats have already been described in detail elsewhere, this mini review focuses solely on peptide-based inhibitors, an emerging class of therapeutic molecules recently applied against some ADAM and ADAMTS members. We describe both linear and cyclic peptide-based inhibitors which have been developed using different approaches ranging from traditional medicinal chemistry and rational design strategies to novel combinatorial peptide-display technologies.

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.

B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein-protein interaction (PPI) between the BCL6BTB and its corepressors has emerged as a therapeutic target for the treatment of DLBCL and a number of other human cancers. This Perspective provides an overview of recent advances in the development of BCL6BTB inhibitors from reversible inhibitors, irreversible inhibitors, to BCL6 degraders. Inhibitor design and medicinal chemistry strategies for the development of novel compounds will be provided. The binding mode of new inhibitors to BCL6BTB are highlighted. Also, the in vitro and in vivo assays used for the evaluation of new compounds will be discussed.

Model-based Target Pharmacology Assessment (mTPA): An Approach Using PBPK/PD Modeling and Machine Learning to Design Medicinal Chemistry and DMPK Strategies in Early Drug Discovery.

The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly dependent on the targeted pharmacology, a relationship that is often not well characterized during early phases of drug discovery. Generic assumptions around PK and potency risk misguiding screening and compound design toward nonoptimal absorption, distribution, metabolism, and excretion (ADME) or molecular properties and ultimately may increase attrition as well as hit-to-lead and lead optimization timelines. The present work introduces model-based target pharmacology assessment (mTPA), a computational approach combining physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling, sensitivity analysis, and machine learning (ML) to elucidate the optimal combination of PK, potency, and ADME specific for the targeted pharmacology. Examples using frequently encountered PK/PD relationships are presented to illustrate its application, and the utility and benefits of deploying such an approach to guide early discovery efforts are discussed.

Insights into Newly Approved Drugs from a Medicinal Chemistry Perspective.

The development of new drugs is becoming notably harder each decade. To overcome the present pitfalls in the drug development pipeline, such as those related to potency, selectivity, or absorption, distribution, metabolism, excretion and toxicity properties, medicinal chemistry strategies need to be in continuous evolution and need to become even more multidisciplinary. In this review, we present how structure-based, ligand-based, and fragment-based drug design (SBDD, LBDD, and FBDD, respectively) and their respective techniques were used for the design and optimization of successful cases of New Molecular Entities (NMEs) approved by the Food and Drug Administration (FDA).

Into the Fray! A Beginner's Guide to Medicinal Chemistry.

Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the well-recited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

Trends in peptide drug discovery.

Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. In this Perspective, we summarize key trends in peptide drug discovery and development, covering the early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry that continue to advance the field. We emphasize lessons from earlier approaches that are still relevant today as well as emerging strategies such as integrated venomics and peptide-display libraries that create new avenues for peptide drug discovery. We also discuss the pharmaceutical landscape in which peptide drugs could be particularly valuable and analyse the challenges that need to be addressed for them to reach their full potential.

Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress

Phosphodiesterase 10A is a member of Phosphodiesterase (PDE)-superfamily of the enzyme which is responsible for hydrolysis of cAMP and cGMP to their inactive forms 5'-AMP and 5'-GMP, respectively. PDE10A is highly expressed in the brain, particularly in the putamen and caudate nucleus. PDE10A plays an important role in the regulation of localization, duration, and amplitude of the cyclic nucleotide signalling within the subcellular domain of these regions, and thereby modulation of PDE10A enzyme can give rise to a new therapeutic approach in the treatment of schizophrenia and other neurodegenerative disorders. Limitation of the conventional therapy of schizophrenia forced the pharmaceutical industry to move their efforts to develop a novel treatment approach with reduced side effects. In the past decade, considerable developments have been made in pursuit of PDE10A centric antipsychotic agents by several pharmaceutical industries due to the distribution of PDE10A in the brain and the ability of PDE10A inhibitors to mimic the effect of D2 antagonists and D1 agonists. However, no selective PDE10A inhibitor is currently available in the market for the treatment of schizophrenia. The present compilation concisely describes the role of PDE10A inhibitors in the therapy of neurodegenerative disorders mainly in psychosis, the structure of PDE10A enzyme, key interaction of different PDE10A inhibitors with human PDE10A enzyme and recent medicinal chemistry developments in designing of safe and effective PDE10A inhibitors for the treatment of schizophrenia. The present compilation also provides useful information and future direction to bring further improvements in the discovery of PDE10A inhibitors.

The emergence of the C-H functionalization strategy in medicinal chemistry and drug discovery.

Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is an important criterion for successful implementation. Despite the rapid ascent of artificial intelligence and computational and bioanalytical techniques to accelerate drug discovery in big pharma, organic synthesis of privileged scaffolds predicted in silico for in vitro and in vivo studies is still considered as the rate-limiting step. C-H activation is the latest technology added into an organic chemist's toolbox for the rapid construction and late-stage modification of functional molecules to achieve the desired chemical and physical properties. Particularly, elimination of prefunctionalization steps, exceptional functional group tolerance, complexity-to-diversity oriented synthesis, and late-stage functionalization of privileged medicinal scaffolds expand the chemical space. It has immense potential for the rapid synthesis of a library of molecules, structural modification to achieve the required pharmacological properties such as absorption, distribution, metabolism, excretion, toxicology (ADMET) and attachment of chemical reporters for proteome profiling, metabolite synthesis, etc. for preclinical studies. Although heterocycle synthesis, late-stage drug modification, 18F labelling, methylation, etc. via C-H functionalization have been reviewed from the synthetic standpoint, a general overview of these protocols from medicinal and drug discovery aspects has not been reviewed. In this feature article, we will discuss the recent trends of C-H activation methodologies such as synthesis of medicinal scaffolds through C-H activation/annulation cascade; C-H arylation for sp2-sp2 and sp2-sp3 cross-coupling; C-H borylation/silylation to introduce a functional linchpin for further manipulation; C-H amination for N-heterocycles and hydrogen bond acceptors; C-H fluorination/fluoroalkylation to tune polarity and lipophilicity; C-H methylation: methyl magic in drug discovery; peptide modification and macrocyclization for therapeutics and biologics; fluorescent labelling and radiolabelling for bioimaging; bioconjugation for chemical biology studies; drug-metabolite synthesis for biodistribution and excretion studies; late-stage diversification of drug-molecules to increase efficacy and safety; cutting-edge DNA encoded library synthesis and improved synthesis of drug molecules via C-H activation in medicinal chemistry and drug discovery.

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.

Synthetic approaches to unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles and their MAO-B inhibitory activity. A review

Selective monoamine oxidase type B (MAO-B) inhibitors are currently used as coadjuvants for treating early motor symptoms of Parkinson’s disease. Aiming at the elucidation of MAO-B inhibitors with 1,3,4-oxadiazole scaffolds, we make a comprehensive update on the new and old chemical methods employed for the synthesis of the unsymmetrical oxadiazole derivatives that lead to high yield compounds. We summarize a state of the selective MAO-B inhibitors with oxadiazole scaffold, describing the results, structures, structure-activity relationships (SARs) and medicinal chemistry strategies over the years. The analysis of the recent papers would facilitate tracking the increasing number of oxadiazole derivatives as new chemical spaces with MAO-B inhibitory potential designed to ensure the safe use of the compounds and elimination of the unwanted drug-drug interactions.

Peptide Late-Stage Diversifications by Rhodium-Catalyzed Tryptophan C7 Amidation

Summary The late-stage diversification (LSD) of structurally complex peptides has emerged as a powerful platform for molecular engineering and drug discovery. Besides traditional peptide modifications, such as native chemical ligations or cross-couplings with prefunctionalized substrates, during recent years, C―H activation has gained considerable momentum as a robust and step-economical strategy for late-stage peptide modifications, thus far predominantly for the formation of C―C bonds. Although C―N bond formations represent established strategies in medicinal chemistry and drug discovery, methods for direct amidations of tryptophan and tryptophan-containing peptides are rare and severely limited to the activated C2 position. In contrast, we herein disclose the first example of direct late-stage peptide C―H amidation reaction and the unprecedented late-stage peptide diversification on tryptophan C7 position in a highly site-selective manner. Moreover, this strategy sets the stage for sequential double C(7)―H/C(2)―H modifications, further improving the peptide structural complexity.

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor*.

Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site‐directed mutagenesis.

Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.

The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound 16 with a 2-methylthiobenzamide. Compound 16 inhibited HDAC3 with an IC50 of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.