Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

Binding Kinetics Survey of the Drugged Kinome.

Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug-target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success. Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be exploited as an optimization strategy. Furthermore, using bio- and chemoinformatics we uncovered structural features influencing rate constants. Our results underscore the value of binding kinetics information in rational drug design and provide a resource for future studies on this subject.

Evaluation of the in vitro release and pharmacokinetics of parenteral injectable formulations for steroids.

The aim of this study was to investigate the pharmacokinetics of injectable conventional dosage forms containing steroids. First, the in vitro release of drospirenone (DRSP) microcrystal suspensions (MCSs) was studied. Next, the pharmacokinetics of selected subcutaneously injected DRSP MCSs was analyzed in female Wistar rats and Cynomolgus monkeys. Furthermore, in vivo and in vitro results were fitted to mathematical models. Although the in vitro-in vivo correlation was partially good, the predictability of the in vitro test was assumed to be restricted. Nevertheless, mathematical calculations and in vitro results allow the interpretation of in vivo results and the identification of parameters influencing the drug release. DRSP microcrystal size had a marginal influence on the pharmacokinetics. The drug absorption was slower from aqueous MCSs than from peanut oil MCSs. Absorption profiles of aqueous DRSP MCSs correlated best with Hixson-Crowell model, whereas absorption profiles of oil-based DRSP MCSs showed a good fit to the Higuchi model. The established assumptions were used to interpret the pharmacokinetics of subcutaneously injected oil-based formulations of the steroid ZK28. In summary, low drug solubility in the vehicle and a high vehicle viscosity were assumed to result in slower and constant drug release.

Gestational influences on the pharmacokinetics of gestagenic drugs: a combined in silico, in vitro and in vivo analysis.

During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.