Selective Sigma-1 Agonist

Candidate Profile:

  • ADV127 is an achiral compound
  • The compound shows a good profile regarding Lipinski’s rule compliance
  • logP 2.92; MW 403.4 g/mol
  • Max. kinetic solubility: 282 µM (pH 7.4)
  • Good stability in neutral and acidic conditions
  • Free base thermodynamic solubility of 11617 µM (pH 2), 515 µM (pH 7.4) and a mp of 108 ºC
  • Non-hygroscopic​
  • The free base has been selected for development
  • The initial synthesis has 6 steps with a 30% overall yields
  • The process is suitable for scale-up
  • Good affinity for σ1 receptor, Ki = 13 nM (n=3)
  • Selectivity vs σ2, Ki (σ2/σ1) = 74x
  • The S1R-BiP interaction is not modified and therefore behaves as an S1R agonist.
  • Functional profile corresponding to σ1 agonist based on the effect in capsaicin 1µg and PGE2 0.125 nmol in mice
  • Selective vs 164 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 in vitro cytotoxicity (up to 100 µM)
  • Cardiac hERG potassium channel: IC50 > 10 µM​
  • No in vitro alert on electrophysiological assays of ion channels related to cardiovascular function up to 10 µM
  • Irwin’s test: no relevant effects (60 mg/kg po, rat & mouse)
  • High metabolic stability is expected in humans
  • Metabolic Stability in liver microsomes HRMDoMoMp=84/63/97/103/96/2% (1h)
  • Metabolic Stability in hepatocytes HRMDoMoMp=88/20/–/62/72/2% (1h)
  • Metabolic Stability in mouse t½=3604 min​ at 1μM
  • CYPs IC50 µM (HLM) ≥250 (1A2); 85-250 (2C9); >250 (2C19); >250 (2D6); 85-250 (3A4)
  • Low potential for metabolism-based drug-drug interactions​
  • High permeability (human Caco-2 cells): Papp389 nm/s. ER 0.8
  • Plasma protein binding in humans similar to rodents (83% vs 83-88%)
  • Good oral exposure in rodents (AUC > 12000 ng.h/mL)
  • Bioavailability in rats: F=83%
  • Brain distribution in rats after oral dosing: AUCbrain/AUCplasma = 2.1
  • Max Non Lethal Dose in mouse:​ 250 mg/kg M & F
  • Genotoxicity in vivo (micronuclei): Negative
  • No alert and well-tolerated in 7-day oral rat toxicity (RDT) at 100 mg/kg/d​ (ongoing study)

Current Indications: