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.
Highlights
As the population ages in developed countries and in countries with fast-growing economies such as the so-called BRICS, which account for around 42% of the world population, the impact of progressive diseases is a global concern
Physicochemical properties and drug likeness In order to assess the drug likeness of our lead compound LDT5, we first describe its in silico ADME profile, a step that is classically performed early, for hit-tolead progression [14]
We discussed other of its properties, predictive of good pharmacokinetics and safety profile
Summary
As the population ages in developed countries and in countries with fast-growing economies such as the so-called BRICS, which account for around 42% of the world population, the impact of progressive diseases is a global concern. Benign prostatic hyperplasia (BPH) has a considerable impact on the health and quality of life of a large portion of aging men [1]. BPH is a nonmalignant progressive enlargement of the prostate and is characterized mainly by stromal hyperplasia in the periurethral transition zone and sympathetic autonomic nervous system hyperactivity [2]. BPH pathophysiology involves a static component caused by prostatic enlargement and a dynamic component due to an increased smooth muscle contraction, and both contribute to the lower urinary tract symptoms suggestive of BPH (LUTS/BPH). Prostatic enlargement may be associated with discomfort, and sexual dysfunction [2]
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