TP0586532

TP0586532
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name 4-[(1R,5S)-6-[2-[4-[3-[[2-[(1S)-1-hydroxyethyl]imidazol-1-yl]methyl]-1,2-oxazol-5-yl]phenyl]ethynyl]-3-azabicyclo[3.1.0]hexan-3-yl]butanoic acid;
CAS Number	2427584-96-9;
PubChem CID	155294517;
ChemSpider	115009295;
ChEMBL	ChEMBL4798122;
PDB ligand	H4R (PDBe, RCSB PDB);
Chemical and physical data
Formula	C26H28N4O4
Molar mass	460.534 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H](C1=NC=CN1CC2=NOC(=C2)C3=CC=C(C=C3)C#CC4[C@H]5[C@@H]4CN(C5)CCCC(=O)O)O;
	InChI InChI=1S/C26H28N4O4/c1-17(31)26-27-10-12-30(26)14-20-13-24(34-28-20)19-7-4-18(5-8-19)6-9-21-22-15-29(16-23(21)22)11-2-3-25(32)33/h4-5,7-8,10,12-13,17,21-23,31H,2-3,11,14-16H2,1H3,(H,32,33)/t17-,21?,22-,23+/m0/s1; Key:PULUMLQUYYSBOR-BOSCWZPRSA-N;

TP0586532 is an experimental antibiotic drug, which acts as a potent and selective inhibitor of the bacterial enzyme UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC). This enzyme is important for the production of Lipid A, a key component of the cell membrane of Gram-negative bacteria. Previous inhibitors of LpxC have failed to progress into clinical trials in humans, mostly because of off-target cardiovascular toxicity, so TP0586532 was based on a different structural class which is hoped to reduce this risk. In animal studies it shows activity against carbapenem-resistant Klebsiella pneumoniae but has not yet progressed into human trials.^[1]^[2]^[3]

References

^ Ushiyama F, Takashima H, Matsuda Y, Ogata Y, Sasamoto N, Kurimoto-Tsuruta R, et al. (January 2021). "Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532". Bioorganic & Medicinal Chemistry. 30: 115964. doi:10.1016/j.bmc.2020.115964. PMID 33385955.
^ Fujita K, Takata I, Yoshida I, Honma Y, Okumura H, Otake K, et al. (May 2022). "Pharmacodynamic target assessment and prediction of clinically effective dosing regimen of TP0586532, a novel non-hydroxamate LpxC inhibitor, using a murine lung infection model". Journal of Infection and Chemotherapy. 28 (5): 635–642. doi:10.1016/j.jiac.2022.01.004. PMID 35131156.
^ Fujita K, Takata I, Yoshida I, Okumura H, Otake K, Takashima H, et al. (February 2022). "TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae". The Journal of Antibiotics. 75 (2): 98–107. doi:10.1038/s41429-021-00486-3. PMID 34837061.

[1] Ushiyama F, Takashima H, Matsuda Y, Ogata Y, Sasamoto N, Kurimoto-Tsuruta R, et al. (January 2021). "Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532". Bioorganic & Medicinal Chemistry. 30: 115964. doi:10.1016/j.bmc.2020.115964. PMID 33385955.

[2] Fujita K, Takata I, Yoshida I, Honma Y, Okumura H, Otake K, et al. (May 2022). "Pharmacodynamic target assessment and prediction of clinically effective dosing regimen of TP0586532, a novel non-hydroxamate LpxC inhibitor, using a murine lung infection model". Journal of Infection and Chemotherapy. 28 (5): 635–642. doi:10.1016/j.jiac.2022.01.004. PMID 35131156.

[3] Fujita K, Takata I, Yoshida I, Okumura H, Otake K, Takashima H, et al. (February 2022). "TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae". The Journal of Antibiotics. 75 (2): 98–107. doi:10.1038/s41429-021-00486-3. PMID 34837061.

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[2]

[3]

See also

References