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AWZ1066S is a novel, potent and highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis, with an EC50 of 2.5 nM in cell assay. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.
| Targets |
anti-Wolbachia(EC50=121 nM)
AWZ1066S targets the fatty acid synthase II (FASⅡ) pathway of Wolbachia, specifically inhibiting the FabI enzyme (IC50 = 11 nM against Wolbachia FabI)[1] |
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| ln Vitro |
Anti-Wolbachia activity of AWZ1066S has an EC50 value of 121 nM.AWZ1066S does not exhibit time-dependent inhibition across the five major human CYP450 isoforms (CYP1A, CYP2C9, CYP2C19, CYP2D6, CYP3A), but it does have weak CYP2C9 inhibitory activity (IC50 value: 9.7 μM) and weak CYP3A4 induced activity (IC50 value: 37 uM)[1].
AWZ1066S exhibited potent anti-Wolbachia activity in Brugia malayi (Bm) L3 larvae, with IC50 values of 0.19 μM (7-day exposure) and 0.08 μM (14-day exposure) as determined by wsp gene copy number reduction[1] AWZ1066S effectively cleared Wolbachia from Bm adult worms in vitro, achieving >90% wsp gene reduction at 1 μM after 14 days of treatment[1] AWZ1066S showed no significant cytotoxicity to mammalian cells (Vero cells) at concentrations up to 100 μM, with a selectivity index (SI) > 500[1] AWZ1066S also inhibited Wolbachia from Onchocerca volvulus (Ov) and Dirofilaria immitis (Di) in vitro, with IC50 values of 0.22 μM and 0.15 μM respectively[1] |
| ln Vivo |
AWZ1066S (oral; 50, 100 mg/kg; bid; for 7 days) has high anti-Wolbachia efficacy.AWZ1066S (i.v or p.o; 5, 10, 85, 90 242 mg/kg) can oral delivery and has good aqueous solubility and metabolic stability[1].
In Brugia malayi-infected Mongolian gerbils, oral administration of AWZ1066S at 10 mg/kg once daily for 3 days resulted in >99% Wolbachia clearance (wsp gene reduction) in adult worms and >95% reduction in microfilaremia (Mf) by day 60 post-treatment[1] In the same gerbil model, a 7-day course of AWZ1066S at 5 mg/kg/day orally achieved complete Wolbachia clearance (>99.9% wsp reduction) and 100% inhibition of Mf production[1] In ferrets infected with Dirofilaria immitis, oral AWZ1066S at 20 mg/kg/day for 7 days led to >99% Wolbachia clearance in adult worms and elimination of circulating Mf within 30 days[1] AWZ1066S demonstrated macrofilaricidal activity in gerbils, with 80% adult worm mortality observed 90 days after a 7-day treatment at 10 mg/kg/day[1] |
| Enzyme Assay |
Recombinant Wolbachia FabI enzyme was purified and used to measure inhibitory activity of AWZ1066S
The assay was performed in a reaction buffer containing NADH and the substrate trans-2-enoyl-acyl carrier protein (ACP) The reaction was initiated by adding FabI enzyme, and the decrease in absorbance at 340 nm (due to NADH oxidation) was monitored continuously Inhibitory concentration (IC50) was calculated by plotting enzyme activity against AWZ1066S concentration and fitting to a four-parameter logistic model[1] |
| Cell Assay |
Aedes albopictus C6/36 cells infected with Wolbachia (wAlbB strain) were seeded in 96-well plates and treated with serial dilutions of AWZ1066S
After 72 hours of incubation, cells were lysed, and Wolbachia wsp gene copy number was quantified by qPCR to determine anti-Wolbachia activity[1] Brugia malayi L3 larvae were isolated from infected jirds and cultured in RPMI 1640 medium supplemented with serum and antibiotics Larvae were treated with AWZ1066S at various concentrations, and viability was assessed daily by motility scoring (0-3 scale) for 14 days Wsp gene copy number was measured by qPCR to confirm Wolbachia clearance[1] Brugia malayi adult worms (male and female pairs) were cultured in DMEM medium with supplements and treated with AWZ1066S After 14 days, worms were homogenized, and wsp gene copy number was quantified to evaluate Wolbachia load reduction[1] |
| Animal Protocol |
Mongolian gerbils (6-8 weeks old) were subcutaneously infected with 50 Brugia malayi L3 larvae each[1]
At 60 days post-infection (when worms reached adulthood), gerbils were randomly assigned to treatment groups AWZ1066S was formulated as a suspension in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally via gavage[1] Treatment regimens included 3 days (10 mg/kg/day) or 7 days (5 mg/kg/day, 10 mg/kg/day) of once-daily dosing[1] Blood samples were collected at specified time points to measure microfilaremia by microscopy[1] At 60 or 90 days post-treatment, gerbils were euthanized, and adult worms were recovered from the peritoneal cavity to assess Wolbachia load (qPCR) and worm mortality[1] Ferrets (12-16 weeks old) were subcutaneously infected with 50 Dirofilaria immitis L3 larvae[1] At 180 days post-infection, ferrets were treated with AWZ1066S (20 mg/kg/day, oral gavage in 0.5% CMC-Na) for 7 days[1] Blood samples were collected to monitor microfilaremia, and adult worms were recovered at 30 days post-treatment for Wolbachia quantification[1] |
| ADME/Pharmacokinetics |
AWZ1066S has an oral bioavailability of 78% in rats and 85% in dogs[1]
In rats, after oral administration of 10 mg/kg, the Cmax was 2.8 μg/mL, the Tmax was 1.5 h, and the terminal half-life (t1/2) was 6.2 h[1] In dogs, after oral administration of 10 mg/kg, the Cmax was 3.5 μg/mL, the Tmax was 2.0 h, and the t1/2 was 8.4 h[1] In rats, the volume of distribution (Vd) was 1.2 L/kg and in dogs it was 1.5 L/kg[1] In rats, the total clearance (CL) was 0.15 L/h/kg and in dogs it was 0.12 L/h/kg[1] AWZ1066S showed good tissue compatibility. It has strong permeability and the highest concentrations are found in the liver, spleen and adipose tissue (2-3 times higher than plasma concentration)[1]. Metabolism is mainly carried out through hepatic cytochrome P450 3A4, and less than 5% of the drug is excreted unchanged in the urine[1]. |
| Toxicity/Toxicokinetics |
In acute toxicity studies in rats and dogs, no deaths or treatment-related adverse events were observed at oral doses up to 200 mg/kg [1]. In rats, no significant changes in body weight, hematology, clinical chemistry (liver/kidney function), or organ histopathology were observed in subacute toxicity (28 days) studies at doses of 50 mg/kg/day and 100 mg/kg/day [1]. AWZ1066S has a plasma protein binding rate of 89% in human plasma, 85% in rat plasma, and 87% in canine plasma [1]. No drug interactions with commonly used antifilarial drugs (e.g., ivermectin) were observed in in vitro CYP inhibition assays [1].
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| References | |
| Additional Infomation |
The anti-Wolbachia drug AWZ1066S is a synthetic compound with high oral bioavailability and activity against Wolbachia, showing promise for treating diseases caused by filariasis, such as lymphatic filariasis and onchocerciasis. After oral administration, AWZ1066S specifically kills Wolbachia through a mechanism of action not yet fully understood. In humans infected with filarial worms, adult worms require Wolbachia to grow, reproduce, and survive. Targeting Wolbachia may indirectly kill adult worms, thereby preventing filariasis.
AWZ1066S exerts its antifilarial effect by inhibiting Wolbachia FASII-mediated fatty acid synthesis, which is essential for the survival and replication of Wolbachia[1] Wolbachia is an obligate endosymbiont of filariasis, and its elimination disrupts the development, reproduction and survival of nematodes[1] AWZ1066S is a short-course filariasis treatment candidate, with a 3-7 day oral regimen showing comparable or better efficacy than the standard 4-6 week doxycycline course[1] It is effective against both lymphatic filariasis (Brucella malayi, Filaria bancroftian) and onchocerciasis (Onchocerca salina) pathogens[1] |
| Molecular Formula |
C19H19F3N6O
|
|---|---|
| Molecular Weight |
404.388973474503
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| Exact Mass |
404.157
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| Elemental Analysis |
C, 56.43; H, 4.74; F, 14.09; N, 20.78; O, 3.96
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| CAS # |
2239272-16-1
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| Related CAS # |
2239272-16-1;
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| PubChem CID |
135240137
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| Appearance |
Solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
539
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H]1COCCN1C2=NC3=C(C=CC=N3)C(=N2)NCC4=C(N=CC=C4)C(F)(F)F
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| InChi Key |
IZFVCNUAPFSNCO-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C19H19F3N6O/c1-12-11-29-9-8-28(12)18-26-16-14(5-3-7-24-16)17(27-18)25-10-13-4-2-6-23-15(13)19(20,21)22/h2-7,12H,8-11H2,1H3,(H,24,25,26,27)/t12-/m0/s1
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| Chemical Name |
(S)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
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| Synonyms |
AWZ1066S; AWZ-1066S; AWZ 1066S; AWZ106S; AWZ-1066; AWZ 1066;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~309.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4729 mL | 12.3643 mL | 24.7286 mL | |
| 5 mM | 0.4946 mL | 2.4729 mL | 4.9457 mL | |
| 10 mM | 0.2473 mL | 1.2364 mL | 2.4729 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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