CRS-3123

Investigational

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

HIDE SMILES / InChI

Molecular Formula	C19H19Br2N3O2S
Molecular Weight	513.246
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Clostridium difficile 3	Inhibitor 8,297
Staphylococcus aureus 67	Inhibitor 8,297
Streptococcus pyogenes 6	Inhibitor 8,297
Enterococcus 3	Inhibitor 8,297
Methionyl-tRNA synthetase, Clostridium difficile 2	Inhibitor 8,297	0.02 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Clostridium infections 2	Curative		Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
352 ng/mL	200 mg single, oral	CRS-3123 plasma	Homo sapiens
507 ng/mL	400 mg single, oral	CRS-3123 plasma	Homo sapiens
654 ng/mL	600 mg single, oral	CRS-3123 plasma	Homo sapiens
470 ng/mL	200 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
731 ng/mL	600 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
3200 ng/mL	400 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
1550 ng × h/mL	200 mg single, oral	CRS-3123 plasma	Homo sapiens
2340 ng × h/mL	400 mg single, oral	CRS-3123 plasma	Homo sapiens
3560 ng × h/mL	600 mg single, oral	CRS-3123 plasma	Homo sapiens
2500 ng × h/mL	200 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
4030 ng × h/mL	600 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
615 ng × h/mL	400 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
3 h	200 mg single, oral	CRS-3123 plasma	Homo sapiens
3.6 h	400 mg single, oral	CRS-3123 plasma	Homo sapiens
5 h	600 mg single, oral	CRS-3123 plasma	Homo sapiens
4.6 h	200 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
6.1 h	600 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens
5 h	400 mg 2 times / day steady-state, oral	CRS-3123 plasma	Homo sapiens

Sourcing

Sourcing

Show entries

Vendor/Aggregator	ID	URL
Axon MedChem	1705	https://www.axonmedchem.com/product/1705
MolPort	MolPort-042-665-742	https://www.molport.com/shop/molecule-link/MolPort-042-665-742
MuseChem	I006300	https://www.musechem.com/product/I006300.html
Toronto Research Chemicals	R144653	https://www.trc-canada.com/product-detail/?CatNum=R144653
eMolecules	275138703	https://orderbb.emolecules.com/search/#?query=275138703

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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
Record UNII	2P987FW4E8
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

CRS-3123

Common Name

English

REP3123

Code

English

5-((3-(((4R)-6,8-DIBROMO-3,4-DIHYDRO-2H-1-BENZOPYRAN-4-YL)AMINO)PROPYL)AMINO)THIENO(3,2-B)PYRIDIN-7(4H)-ONE

Systematic Name

English

REP-3123

Code

English

CRS3123

Code

English

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Code System

Code

Type

Description

FDA UNII

2P987FW4E8

PRIMARY

PUBCHEM

16744283

PRIMARY

CAS

1013915-71-3

PRIMARY

CLINICAL_TRIALS.GOV

CRS-3123

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.

DRUG BANK

DB12262

PRIMARY

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Related Record

Type

Details


					PJX89V9R6N

CLOSTRIDIUM DIFFICILE

TARGET ORGANISM->INHIBITOR

Comments:

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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Related Record

Type

Details


					2P987FW4E8

CRS-3123

ACTIVE MOIETY

Comments:

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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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2