Bispecific Sigma-1 Agonist and Sigma-2 Antagonist
Candidate Profile:
- ADV368 is an achiral compound
- The compound shows a good profile regarding Lipinski’s rule compliance
- logP 1.44; MW 478.6 g/mol
- Max. kinetic solubility: 300 µM (pH 7.4)
- Good stability in neutral and acidic conditions
- Free base thermodynamic solubility of 5237 µM (pH 2) and 901 µM (pH 7.4) and a mp of 168 ºC
- The free base has been selected for development
- Synthesis has 4 steps with a 70% overall yield
- The process is suitable for scale-up
- Good affinity for σ1 receptor, Ki = 46 nM
- Good affinity for σ2 receptor, Ki = 14 nM
- S1R-BIP interaction is not modified and, therefore, behaves as an S1R agonist
- Functional profile corresponding to σ1 agonist and σ2 antagonist based on the effect in capsaicin 1µg i.pl. in WT and KO 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)
- High metabolic stability expected in humans
- Metabolic Stability in liver microsomes HRMDoMoMp=96/84/92/93/61/73% (1h)
- Metabolic Stability in hepatocytes HRMDoMoMp=94/82/–/99/22/48% (1h)
- Metabolic Stability in mouse t½=871 min at 1μM
- CYPs IC50 µM (HLM) >250 (1A2,2D6,3A4)
- Low potential for metabolism-based drug-drug interactions
- Moderate permeability (human Caco-2 cells): Papp 106nm/s. ER 3.3
- Plasma protein binding in humans similar to rodents (37% vs 48-51%)
- Good oral exposure in rodents (AUC > 2000 ng.h/mL)
- Bioavailability in rats: F=117%
- Brain distribution in rats after oral dosing: AUCbrain/AUCplasma = 0.5
- Urinary excretion in the rat is a minor route of elimination (12% of unchanged compound excreted)
- Fast oral absorption in dogs
- High exposure after oral administration in dogs, with no clinical signs observed
- Moderate elimination rate with t1/2 of 3h after iv administration in dogs
- Medium hepatic extraction ratio in dogs, suggesting that clearance could be limited by and dependent upon liver blood flow
- Volume of distribution higher than the total body wate in dogs, indicating a good distribution of the compound
- Good bioavailability in dogs (67%)
- Max Non Lethal Dose in mouse: 2000 mg/kg M & F
- Genotoxicity in vivo (micronuclei): Negative
- No alert and well-tolerated in 7-day oral rat toxicity (RDT) at 10 (F) & 50 (M) mg/kg/d
Current Indications: