Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism.

Through a computer monitor darkly: artificial intelligence in absorption, distribution, metabolism and excretion science.

Artificial Intelligence (AI) is poised or has already begun to influence absorption, distribution, metabolism and excretion (ADME) science. It is not in the area expected - that of superior modelling of ADME data to increase its predictive power. It is influencing traditional exhaustive and careful literature research by providing almost perfect summaries of existing information.

Anti-infectives Developed as Racemic Drugs in the 21st Century: Norm or Exception?

This viewpoint outlines the case for developing new chemical entities (NCEs) as racemates in infectious diseases and where both enantiomers and racemate retain similar on- and off-target activities as well as similar PK profiles. There are not major regulatory impediments for the development of a racemic drug, and minimizing the manufacturing costs becomes a particularly important objective when bringing an anti-infective therapeutic to the marketplace in the endemic settings of infectious diseases.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water.

Correction: Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

Correction for 'Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines' by Patrick Kielty et al., Chem. Commun.

The Critical Role of Passive Permeability in Designing Successful Drugs.

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology.

An in vitro toolbox to accelerate anti-malarial drug discovery and development.

Background: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.

Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

In nature, the unmasking of heterocyclic quinones to form stabilized quinone methide radicals is achieved using reductases (bioreduction). Herein, an alternative controllable room-temperature, visible-light activated protocol using alkoxyamines and bis-alkoxyamines is provided. Selective synthetic modification of the bis-alkoxyamine, allowed chromophore deactivation to give one labile alkoxyamine moiety.

The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes.

Intracellular and Intraorgan Concentrations of Small Molecule Drugs: Theory, Uncertainties in Infectious Diseases and Oncology, and Promise.

The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment.

Clearance in Drug Design.

Due to its implications for both dose level and frequency, clearance rate is one of the most important pharmacokinetic parameters to consider in the design of drug candidates. Clearance can be classified into three general categories, namely, metabolic transformation, renal excretion, and hepatobiliary excretion. Within each category, there are a host of biochemical and physiological mechanisms that ultimately determine the clearance rate.

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

The 2-aminopyridine MMV048 was the first drug candidate inhibiting phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant and clinical isolates.

Importance of target-mediated drug disposition for small molecules.

Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance.

Selective Methylmagnesium Chloride Mediated Acetylations of Isosorbide: A Route to Powerful Nitric Oxide Donor Furoxans.

Isosorbide was functionalized with furoxan for the first time to give adducts that release nitric oxide up to 7.5 times faster than the commercial vasodilator, isosorbide-5-mononitrate (Is5N). The synthesis was facilitated by MeMgCl-mediated selective acetylation of isosorbide or selective deacetylation of isosorbide-2,5-diacetate, which was rationalized in terms of a more stable 5-alkoxide magnesium salt using DFT.

Safety Assessment of Acyl Glucuronides-A Simplified Paradigm.

While simple - (ether-linked) and -glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of the parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging.

Relevance of Half-Life in Drug Design.

Drug half-life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A half-life of 12-48 h is generally ideal for once daily dosing of oral drugs. If the half-life is too short, it may require more frequent dosing in order to maintain desired exposures and avoid unnecessarily high peak concentrations.

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P.

Volume of Distribution in Drug Design.

Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic molecule will tend to exhibit higher volume of distribution than a neutral molecule.

Which metabolites circulate?

Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites.

Evolution of ADME science: where else can modeling and simulation contribute?

The commentary describes progress in modeling and simulation in ADME science and focuses on lipoidal permeability as a central driver of drug molecule disposition. The tension between screening and in silico is outlined with practical suggestions on how to improve multiparameter models. The limitations on modeling drug metabolism and its enzymes are highlighted together with key features in molecules that lead to drug transport.