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 i.pl. and PGE2 0.125 nmol i.pl. 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: