ADV462

Selective Sigma-2 Antagonist

Candidate Profile:

  • ADV462 is an achiral compound ​
  • The compound shows a good profile regarding Lipinski’s rule compliance
  • logP 1.74; MW 399.5 g/mol​
  • Max. kinetic solubility: >996 µM (pH 7.4)
  • Good stability in neutral and acidic conditions
  • Free base thermodynamic solubility of ≥7935 µM (pH 2), 16641 µM (pH 7.4)​ and a mp of 134 ºC
  • Non-hygroscopic​
  • The free base has been selected for development
  • Synthesis has 5 steps with a 30% overall yield
  • The process is suitable for scale-up
  • Good affinity for σ2 receptor, Ki = 13 nM ​
  • Selectivity vs σ1, Ki (σ1/σ2) = 137x
  • Functional profile corresponding to σ2 antagonist based on the effect in capsaicin 1µg i.pl. in WT and KO mice
  • Selectivity vs 5-HT1A, 5-HT2B, α1A, α2A, H1, α2δ–1, α2δ–2, DAT, NET, SERT, δ-opioid, κ-opioid, µ-opioid (inhib.<50% at 1 µM)​
  • Selective vs 167 targets panel (inhib.<50% at 10 µM)
  • No alerts on genotoxicity in vitro: SOS/umu, Ames, and CHO micronucleus tests negative​
  • No alerts on mitochondrial toxicity
  • No alerts on phospholipidosis
  • No alerts on in vitro cytotoxicity (up to 100 µM)
  • Cardiac hERG potassium channel: IC50 > 100 µM​
  • No in vitro alert on electrophysiological assays of ion channels related to cardiovascular function up to 100 µM
  • Irwin’s test: no relevant effects (60 mg/kg po, rat & mouse)
  • High metabolic stability expected in humans
  • Metabolic Stability in liver microsomes HRMDoMoMp=93/95/93/86/24/64% (1h)
  • Metabolic Stability in hepatocytes HRMDoMoMp=79/2/–/48/0.05/34% (1h)
  • Metabolic Stability in mouse t½=546 min​ at 1μM
  • CYPs IC50 µM (HLM) >>900 (1A2); 300-900 (2C9); >900 (2C19); 133 (2D6); >920 (3A4)​
  • Low potential for metabolism-based drug-drug interactions​
  • High permeability (human Caco-2 cells): Papp 177nm/s. ER 1.2
  • Plasma protein binding in humans lower than in rodents (31% vs 60-67%)
  • Good oral exposure in rodents (AUC > 2000 ng.h/mL)
  • Bioavailability in rats: F=51%
  • Brain distribution in rats after oral dosing: AUCbrain/AUCplasma > 0.3
  • Metabolism in rats: phase I (oxidations, hydrolysis)
  • Low urinary excretion in the rat (21% of oral dose)
  • Very fast oral absorption in dogs
  • High exposure after oral administration in dogs, with no clinical signs observed
  • Fast elimination with t1/2 of 1h after iv administration in dogs
  • Clearance higher than hepatic blood flow in dogs (1900 mL/h/kg) was observed with a mean CL value of 2906 mL/h/kg, suggesting that the elimination of WLB-89462 could not be limited to hepatic clearance.
  • Volume of distribution is higher than the total body water in dogs, indicating a good distribution of the compound
  • Almost complete bioavailability in dogs (89%)
  • Max Non Lethal Dose in mouse:​ 500 mg/kg M & F
  • Genotoxicity in vivo (micronuclei): Negative
  • No alert and well-tolerated in 7-day oral rat toxicity (RDT) at 100 & 400 mg/kg/d​

Current Indications: