CDRI 830

CDRI S006-830

N-[2-[4-[(4-methoxyphenyl)-thiophen-2-ylmethyl]phenoxy]ethyl]-N-propan-2-ylpropan-2-amine

CDRI-830 of thiophene containing trisubstituted methane (TRSM) class was identified as an anti-tubercular lead with MIC value of 1.33 mg/L against Mycobacterium tuberculosis H37Rv strain, non-toxicity against Vero C-1008 cell line (selectivity index >10), ex vivo efficacy (in mouse and human macrophages) equivalent to first line TB drugs, lung CFU count (2.2×107) comparable to pyrazinamide (1.9×107) and ethambutol (1.27×107). CDRI-830 has exhibited potent bactericidal activity against single and multi-drug resistant clinical isolates of M. tuberculosis. Furthermore, CDRI-830 has demonstrated good pharmacokinetic properties with fast intestinal absorption, peak plasma concentration one hour post oral dose, optimum elimination half-life (9-13 h), plasma protein binding (~60%), favorable bioavailability (45-50%) and mean residence time (18-20 h).

CDRI S006-830 is a potent triethylamine containing thiophene antitubercular compound of the Central Drug Research Institute, India. The present study aimed to conduct comprehensive metabolic investigations of CDRI S006-830 to corroborate its preclinical investigations. Preliminary metabolic investigations were performed to assess the metabolic stability, enzyme kinetics, reaction phenotyping, and metabolite identification of CDRI S006-830 in rat, rabbit, dog, and human liver microsomes using liquid chromatography with mass spectrometry. The observed in vitro t_1/2 and Cl_int values were 9.9 ± 1.29, 4.5 ± 0.52, 4.5 ± 0.86, 17 ± 5.21 min and 69.60 ± 8.37, 152.0 ± 17.26, 152.34 ± 27.63, 33.62 ± 21.04 μL/min/mg in rat, rabbit, dog and human liver microsomes respectively. These observations suggested that CDRI S006-830 rapidly metabolized in the presence of NADPH in liver microsomes of rat, rabbit and dog while moderately metabolized in human liver microsomes. It was observed that CDRI S006-830 exhibited monophasic Michaelis–Menten kinetics. The metabolism of CDRI S006-830 was primarily mediated by CYP3A4 and was deduced by CYP reaction phenotyping with known potent inhibitors. CYP3A4 involvement was also confirmed by cDNA-expressed recombinant human isozyme activity with different CYPs. Four major phase-I metabolites of S006-830, (M-1 to M-4) were detected in rat, rabbit, dog (except M4) and human liver microsomes……..http://onlinelibrary.wiley.com/doi/10.1002/dta.1802/abstract?systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+14th+May+11%3A00-14%3A00+BST+%2F+06%3A00-09%3A00+EDT+%2F+18%3A00-21%3A00+SGT+for+essential+maintenance.Apologies+for+the+inconvenience.

13C NMR

The triarylmethane antituberculosis drug CDRI-830 is synthesized. The triarylmethane derivative 4 is prepared from ether 6 by a rearrangement process. The total synthesis of the drug CDRI-830 is achieved in a good overall yield of 35% from a simple thiophene derivative 8.

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry Volume 44, Issue 23, 2014

 

Total Synthesis of an Experimental Antitubercular DrugDOI:

10.1080/00397911.2014.942745

Uma Reddy Pailla^ab, Veera Reddy Arava^a* & L. K. Ravindranath^b

pages 3408-3413

http://www.tandfonline.com/doi/abs/10.1080/00397911.2014.942745

REFERENCES

http://www.ingentaconnect.com/content/ben/cpa/2015/00000011/00000001/art00008?crawler=true

S006-830 against H37RV, single, multi-drug resistant M. tuberculosis; CFU in the lungs with S006-830, EMB, PZA (European Journal of Medicinal Chemistry 2015, 95, 357-368, J Antimicrob Chemother. 2012; 67(5):1188-97, Bioorg Med Chem Lett, 2008, 18, 289-292)

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