Lead Quality

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection

“…We used LLE to drive compound design during lead generation, and although it was a useful parameter, it did not discriminate the quality difference between ( S )- 13 and ( S )- 15 , which have similar LLEs but differ markedly in their metabolic stability. We therefore complemented LLE by early estimates of daily dose to man (eD2M, eq ) going forward to assess the overall compound quality before designing the next generation of compounds and selection of promising compounds for evaluation in in vivo models (pharmacokinetic (PK), pharmacodynamic (PD) and safety). − This strategy was motivated by a desire both to keep the dose below 100 mg/day, which could have an impact on the maximal achievable clinical efficiency versus off-target related safety margins, and a desire to keep cost of goods as low as possible.where eD2M is the early dose to man, IC 50 is the potency in the hMR GAL4 reporter gene antagonist assay, X is the offset factor between in vivo and in vitro IC 50 on the basis of clinical data for eplerenone and spironolactone, CL is the predicted human hepatic clearance, T is the dosing interval, F is the bioavailability, CL int is the intrinsic clearance in human hepatocytes (hHep), and Q h is the hepatic blood flow.…”