Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C19H19Br2N3O2S |
| Molecular Weight | 513.246 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
BrC1=CC(Br)=C2OCC[C@@H](NCCCNC3=CC(=O)C4=C(N3)C=CS4)C2=C1
InChI
InChIKey=NNTYBKTXMKBRFA-CQSZACIVSA-N
InChI=1S/C19H19Br2N3O2S/c20-11-8-12-14(2-6-26-18(12)13(21)9-11)22-4-1-5-23-17-10-16(25)19-15(24-17)3-7-27-19/h3,7-10,14,22H,1-2,4-6H2,(H2,23,24,25)/t14-/m1/s1
| Molecular Formula | C19H19Br2N3O2S |
| Molecular Weight | 513.246 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: Description was created based on several sources, including
http://adisinsight.springer.com/drugs/800027088 | https://www.ncbi.nlm.nih.gov/pubmed/19258353
Curator's Comment: Description was created based on several sources, including
http://adisinsight.springer.com/drugs/800027088 | https://www.ncbi.nlm.nih.gov/pubmed/19258353
CRS-3123, also known as REP-3123, is a methionyl-tRNA synthetase inhibitor potentially for the treatment of enteric infections. CRS-3123 is in Phase 1 clinical development for the treatment of Clostridium difficile Infection (CDI). CRS-3123 is a small molecule protein synthesis inhibitor that acts on the novel target methionyl-tRNA synthetase (MetRS). REP-3123 has been shown to be active in vitro against clinical
isolates of C. difficile including epidemic strains such as B1/
NAP1/027; MIC values of REP-3123 for C. difficile are
typically 0.5 -- 1.0 mg/l. REP-3123 is also active against a range of clinically important aerobic Gram-positive bacteria
including methicillin-susceptible and -resistant Staphylococcus
aureus (MIC90 values of 0.06 and 0.25 mg/l, respectively),
Streptococcus pyogenes (MIC90 0.5 mg/l) and enterococci
(MIC90 32 mg/l). CRS-3123 has numerous potential advantages over current CDI therapies. In addition to being highly potent against all clinical isolates of C. difficile tested, CRS-3123 has several desirable qualities for the treatment of CDI which include:
Narrow spectrum for C. difficile, which may substantially reduce the disruption of normal intestinal flora compared to current therapies;
Inhibition of toxin production, potentially leading to lower morbidity and mortality;
Inhibition of sporulation, potentially leading to lower rates of transmission and recurrence;
A novel mechanism of action, which means that its use will not compromise the utility of systemic antibiotics while maintaining activity against pre-existing resistance mechanisms.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL614965 |
|||
Target ID: CHEMBL352 |
|||
Target ID: CHEMBL356 |
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Target ID: CHEMBL612318 |
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Target ID: Methionyl-tRNA synthetase, Clostridium difficile |
0.02 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Curative | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
352 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
507 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
654 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
470 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
731 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
3200 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1550 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
2340 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
3560 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
2500 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
4030 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
615 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
3.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
4.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
6.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31685472 |
400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
CRS-3123 plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Sample Use Guides
CRS-3123 will be supplied in 100 and 200 milligram capsules. Subjects randomized to active drug in Cohorts A through E will receive 100 mg, 200 mg, 400 mg, 800 mg and 1200 mg respectively, as a single oral dose.
Route of Administration:
Oral
MIC values of CRS-3123 for C. difficile are
typically 0.5 -- 1.0 mg/l. CRS-3123 is also active against a range of clinically important aerobic Gram-positive bacteria
including methicillin-susceptible and -resistant Staphylococcus
aureus (MIC90 values of 0.06 and 0.25 mg/l, respectively),
Streptococcus pyogenes (MIC90 0.5 mg/l) and enterococci
(MIC90 10-fold reduction in the sporulation rate in vitro
| Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 10:29:02 GMT 2023
by
admin
on
Sat Dec 16 10:29:02 GMT 2023
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| Record UNII |
2P987FW4E8
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| Record Status |
Validated (UNII)
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| Record Version |
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16744283
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CRS-3123
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PRIMARY | Detailed Description: This is a Phase I, multi-center, placebo-controlled, double-blind, dose-escalation study to evaluate the safety and tolerability of CRS3123, a methionyl-tRNA synthetase inhibitor. Since this is a FIH study of a new class of drugs, the maximum safe starting dose was estimated from the NOAEL from preclinical studies in accordance with FDA guidance documents (FDA Guidance for Industry, July 2005). A very low starting dose has been chosen. In the initial Cohorts, doses of 100, 200 and 400 will be given, all are below the estimated human starting dose. If any significant safety signals are encountered, the investigators will notify the SMC and call for a review. Dose escalation to Cohorts D and E will require a full SMC review of all safety data obtained through Day 7 for the preceding Cohorts. Forty healthy male and female subjects 18 to 45 years, inclusive, will be admitted for an inpatient study. Each subject will receive a single oral dose of CRS3123 or placebo. There will be 8 patients for each cohort (6 active, 2 placebo). The ascending doses are 100, 200, 400, 800 and 1200 mg respectively for cohorts A through E. | ||
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DB12262
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TARGET ORGANISM->INHIBITOR |
RESULTS: REP3123 was active against a collection of 108 clinical isolates of C. difficile and against epidemic, moxifloxacin-resistant BI/NAP1/027 strains (MIC range=0.5-1 mg/L and MIC(90) = 1 mg/L). The spectrum of activity included clinically important aerobic Gram-positive cocci such as Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecalis and Enterococcus faecium (MIC(90)s < 1 mg/L), but REP3123 was not active against most Gram-negative bacteria. REP3123 targeted C. difficile MetRS with a calculated inhibition constant (K(i)) of 0.020 nM, and selectivity was >1000-fold over human mitochondrial and cytoplasmic MetRS. The specific mode of action within bacterial cells was demonstrated by macromolecular synthesis assays that showed inhibition of protein synthesis by REP3123, and by metS overexpression, which resulted in a 16-fold increase in MIC for REP3123. Spontaneous REP3123-resistant mutants of C. difficile (MICs, 4-128 mg/L) arose with frequencies of 10(-8)-10(-9) and harboured distinct point mutations within the metS gene, resulting in 13 different amino acid substitutions. Most of the MetRS substitutions caused reduced catalytic efficiency and a growth fitness burden.
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ACTIVE MOIETY |
METHODS: Clostridial toxin levels were determined qualitatively using monoclonal antibodies and by cytotoxicity assays. Spores were detected by staining and by quantitative dilution plating after ethanol treatment. Efficacy of REP3123 was tested in a clindamycin-induced C. difficile hamster gastrointestinal (GI) infection model.
RESULTS: REP3123 at concentrations as low as 1 mg/L inhibited de novo toxin production in high cell density, stationary phase cultures of C. difficile. Among comparator agents currently used for CDI therapy, vancomycin required much higher levels of 20 mg/L, and metronidazole had no effect on toxin levels. REP3123 caused a >10-fold reduction of the sporulation rate in vitro. Vancomycin and, in particular, metronidazole appeared to promote the formation of spores. REP3123, at concentrations as low as 0.5 mg/kg, demonstrated efficacy in the hamster model of CDI and was superior to vancomycin in the overall survival of the animals at the end of the study (33 days).
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