Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates.

The delivery of a drug to a specific organ or tissue at an efficacious concentration is the pharmacokinetic (PK) hallmark of promoting effective pharmacological action at a target site with an acceptable safety profile. Sub-optimal pharmaceutical or ADME profiles of drug candidates, which can often be a function of inherently poor physicochemical properties, pose significant challenges to drug discovery and development teams and may contribute to high compound attrition rates. Medicinal chemists have exploited prodrugs as an informed strategy to productively enhance the profiles of new chemical entities by optimizing the physicochemical, biopharmaceutical, and pharmacokinetic properties as well as selectively delivering a molecule to the site of action as a means of addressing a range of limitations. While discovery scientists have traditionally employed prodrugs to improve solubility and membrane permeability, the growing sophistication of prodrug technologies has enabled a significant expansion of their scope and applications as an empowering tool to mitigate a broad range of drug delivery challenges. Prodrugs have emerged as successful solutions to resolve non-linear exposure, inadequate exposure to support toxicological studies, pH-dependent absorption, high pill burden, formulation challenges, lack of feasibility of developing solid and liquid dosage forms, first-pass metabolism, high dosing frequency translating to reduced patient compliance and poor site-specific drug delivery. During the period 2012-2022, the US Food and Drug Administration (FDA) approved 50 prodrugs, which amounts to 13% of approved small molecule drugs, reflecting both the importance and success of implementing prodrug approaches in the pursuit of developing safe and effective drugs to address unmet medical needs.

Examining the Scope of Deriving ß-Aryl Enones from Enol Silanes as Ketone Equivalents via Pd(II)-Mediated Sequential Dehydrosilylation and Arylation.

Silyl enol ethers were examined as a masked source of saturated ketones to derive ß-aryl enones and their derivatives by dehydrosilylation to generate enones in situ and subsequent oxidative arylation with arylboronic acids as transmetallation coupling partners using relayed Pd(II) catalysis in one pot under base-free conditions. Oxygen was found to be an efficient and green oxidant to enable both dehydrosilylation of enol silanes and arylation. Additionally, arylation conditions can be custom-designed to take advantage of aryl halides as an alternative source of arylating agents. The preparative scope was investigated with 35 examples (up to 95% yield), and mechanistic studies implied a cationic Pd(II)-based catalytic system.

Electrophilic Hydrazination of Cyclopropanols Using Azodicarboxylates via Copper(II) Catalysis: An Umpolung Strategy to Access ß-Hydrazino Ketone Motifs.

The scope of an umpolung approach to expand synthetic access to bifunctional γ-keto hydrazine intermediates via electrophilic amination of ß-homoenolates derived from cyclopropanol precursors that took advantage of azodicarboxylates or azodicarboxamides as electron-deficient nitrogen sources was examined. This new synthetic procedure avails commercially available or readily accessible starting materials along with a ligand-free Cu(II) salt as an inexpensive catalyst. Using this operationally simple reaction, which proceeds under mild conditions (open-flask and ambient temperature) and is suitable for multigram scale, preparative applications were established with a range of aryl- and alkyl-substituted cyclopropanols and azodicarboxylate/azodicarboxamide substrates (26 examples, 74-95% yields). Further, the obtained products have been shown to provide convenient synthetic access to γ-hydroxy hydrazide, γ-amino hydrazide, and heterocyclic derivatives.

Synthetic Access to α-Oxoketene Aminals by the Nucleophilic Addition of Enol Silane-Derived Palladium(II) Enolates to Carbodiimides.

Synthetically important α-oxoketene aminal intermediates can now be accessed from readily available and inexpensive carbodiimides as starting materials via the nucleophilic addition of palladium enolates derived from enol silane precursors. This operationally simple method features mild reaction conditions, including open air atmosphere, ligand-free metal catalysis, broad substrate scope, and multi-gram scalability. Select synthetic applications that take advantage of the enamine character of α-oxoketene aminals and involve C-nucleophilic additions to electrophilic systems, including an α,ß-unsaturated ester, an azo dicarboxylate, an aralkyl halide, and an aldehyde, are demonstrated.

Orchestrating a ß-Hydride Elimination Pathway in Palladium(II)-Catalyzed Arylation/Alkenylation of Cyclopropanols Using Organoboron Reagents.

The scope of chemoselective ß-hydride elimination in the context of arylation/alkenylation of homoenolates from cyclopropanol precursors using organoboronic reagents as transmetalation coupling partners was examined. The reaction optimization paradigm revealed a simple ligand-free Pd(II) catalytic system to be most efficient under open air conditions. The preparative scope, which was investigated with 48 examples, supported the applicability of this reaction to a wide range of substrates tolerating a variety of functional groups while delivering ß-substituted enone and dienone derivatives in 62-95% yields.

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design.

The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration.

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo.

Utility of Organoboron Reagents in Arylation of Cyclopropanols via Chelated Pd(II) Catalysis: Chemoselective Access to ß-Aryl Ketones.

Organoborane reagents were investigated as coupling partners to cyclopropanol-derived ß-ketone enolates in the presence of a chelated Pd(II) catalyst. Efficient coupling of a range of electronically and sterically diverse cyclopropanols and aryl/alkenyl boronic derivatives (39 examples, 65-94% yield) could be achieved with the generation of synthetically important ß-aryl ketone intermediates in a chemoselective fashion. This reactivity paradigm, which broadens the scope of aryl donor partners to homoenolates, allows open-flask conditions, water as a cosolvent, and preparation of halogen-bearing ß-aryl ketones that are distinct from previous methods. This chelated Pd(II) catalysis appears to be different from the Pd(0) pathway, as evident from deuterium scrambling studies that could reveal differentiating protonolysis of an α-keto carbopalladium complex in the terminal step.

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir.

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges.

Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties.

Combination antiretroviral therapy (cART) is currently the most effective treatment for HIV-1 infection. HIV-1 protease inhibitors (PIs) are an important component of some regimens of cART. However, PIs are known for sub-optimal ADME properties, resulting in poor oral bioavailability. This often necessitates high drug doses, combination with pharmacokinetic enhancers and/or special formulations in order to effectively deliver PIs, which may lead to a high pill burden and reduced patient compliance. As a remedy, improving the ADME properties of existing drugs via prodrug and other approaches has been pursued in addition to the development of next generation PIs with improved pharmacokinetic, resistance and side effect profiles. Phosphate prodrugs have been explored to address the solubility-limiting absorption and high excipient load. Prodrug design to target carrier-mediated drug delivery has also been explored. Amino acid prodrugs have been shown to improve permeability by engaging active transport mechanisms, reduce efflux and mitigate first pass metabolism while acyl migration prodrugs have been shown to improve solubility. Prodrug design efforts have led to the identification of one marketed agent, fosamprenavir, and clinical studies with two other prodrugs. Several of the reported approaches lack detailed in vivo characterization and hence the potential preclinical or clinical benefits of these approaches are yet to be fully determined.