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
DescriptionSources: http://www.crestonepharma.com/index.php/cdi | https://www.ncbi.nlm.nih.gov/pubmed/20698814Curator's Comment: Description was created based on several sources, including
http://adisinsight.springer.com/drugs/800027088 | https://www.ncbi.nlm.nih.gov/pubmed/19258353
Sources: http://www.crestonepharma.com/index.php/cdi | https://www.ncbi.nlm.nih.gov/pubmed/20698814
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 =0.03 mg/l), but was not active against aerobic
Gram-negative bacteria such as Enterobacteriaceae and nonfermenting
bacilli (MIC values > 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 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20698814 |
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Target ID: CHEMBL352 |
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Target ID: CHEMBL356 |
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Target ID: CHEMBL612318 |
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Target ID: Methionyl-tRNA synthetase, Clostridium difficile Sources: https://www.ncbi.nlm.nih.gov/pubmed/20698814 |
0.02 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Curative | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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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 |
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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
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01551004
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 =0.03 mg/l). At concentrations of 1 mg/l, CRS-3123 inhibited de novo toxin production in high cell density,
stationary phase cultures of C. difficile and also caused
a > 10-fold reduction in the sporulation rate in vitro
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2P987FW4E8
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16744283
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1013915-71-3
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CRS-3123
Created by
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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
Created by
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ACTIVE MOIETY