ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

Abstract

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

Revisiting the Pharmacodynamic Uroselectivity ofα1-Adrenergic Receptor Antagonists

“…This concern is also strengthened by the relatively high affinity we reported here for LDT5 binding to the D 3 receptor. Considering these data, LDT5 is no more considered as the ideal lead compound since the permeability assay with MDCK-MDR1 showed that it is not a substrate of P-glycoprotein (Noël et al, 2016). However, we suggest that the rationale of such a multitarget drug for BPH treatment is maintained mainly based on our previous data with cells from BPH patients, since LDT5…”

SCREENER, an educational game for teaching the Drug Discovery and Development process

“…SCREENER has been conceived as a collaborative project between people with experience on the theoretical aspects of the theme ( 8 - 10 ), experts in ludology with prior experience in game designing and production ( 13 ), and people from the artistic design field. The idea matured after five years of using a board game in a discipline of the Postgraduate Program in Pharmacology and Medicinal Chemistry (PPGFQM) at the Federal University of Rio de Janeiro, Brazil.…”