Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.

Rational design, synthesis and biological profiling of new KDM4C inhibitors.

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.

Investigating the barriers to bioavailability of macrolide antibiotics in the rat.

The aim of this study was to compare the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability for macrolide antibiotics erythromycin, clarithromycin, roxithromycin and telithromycin. In this study, the in vitro metabolic stability in rat liver microsomes and hepatocytes, as well as the in vivo pharmacokinetics in rats were determined following intravenous, intraportal, oral and intraduodenal routes of administration. Pharmacokinetic parameters were calculated for each compound for each route of administration. In vitro metabolic stability studies point to low intrinsic clearance of the tested macrolides in both microsomes (<1 mL/min/g) and hepatocytes (<1 mL/min/g), indicating good stability. The oral bioavailability in rat was low to moderate (14, 36, 36 and 25% for erythromycin, clarithromycin, roxithromycin and telithromycin, respectively). Upon intraduodenal dosing, the bioavailability increased by 1.3-3-fold, the highest increase being with roxithromycin, suggesting some loss due to gastric instability. Following portal vein administration, no hepatic first pass effect was observed with roxithromycin, less than 10% with telithromycin, and ca. 20 and 25% for clarithromycin and erythromycin. Our data showed that the tested macrolides display good in vitro metabolic stability, as was confirmed in vivo where a low hepatic first pass effect was observed. The limited oral bioavailability is likely due to poor oral absorption and/or intestinal first pass metabolism.