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 |
Approval Year
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 10:29:02 UTC 2023
by
admin
on
Sat Dec 16 10:29:02 UTC 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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-
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2P987FW4E8
Created by
admin on Sat Dec 16 10:29:02 UTC 2023 , Edited by admin on Sat Dec 16 10:29:02 UTC 2023
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16744283
Created by
admin on Sat Dec 16 10:29:02 UTC 2023 , Edited by admin on Sat Dec 16 10:29:02 UTC 2023
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1013915-71-3
Created by
admin on Sat Dec 16 10:29:02 UTC 2023 , Edited by admin on Sat Dec 16 10:29:02 UTC 2023
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CRS-3123
Created by
admin on Sat Dec 16 10:29:02 UTC 2023 , Edited by admin on Sat Dec 16 10:29:02 UTC 2023
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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
admin on Sat Dec 16 10:29:02 UTC 2023 , Edited by admin on Sat Dec 16 10:29:02 UTC 2023
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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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