Iclaprim

Iclaprim
Systematic (IUPAC) name
(RS)-5-[(2- cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl]pyrimidine-2,4-diamine
Clinical data
  • Investigational
Oral, intravenous
Pharmacokinetic data
Bioavailability Good (oral)[1]
Identifiers
192314-93-5 Yes
J01EA03
PubChem CID 213043
ChemSpider 184736 
UNII 42445HUU0O 
KEGG D08337 Yes
ChEMBL CHEMBL134561 
Chemical data
Formula C19H22N4O3
354.403 g/mol
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Iclaprim (INN), codenamed AR-100 and RO-48-2622, is a diaminopyrimidine dihydrofolate reductase (DHFR)-inhibiting extended-spectrum antibiotic active against gram positive organisms being developed for the treatment of complicated skin and soft tissue infections caused by antibiotic-resistant bacteria.[2] It is structurally related to trimethoprim. In Phase III clinical trials, intravenously-administered iclaprim was found to be as effective as and better tolerated than linezolid in people with skin and soft tissue infections, many caused by methicillin-resistant Staphylococcus aureus (MRSA).[3][4] In vitro, iclaprim is highly active against MRSA, vancomycin-resistant Staphylococcus aureus (VRSA), strains of Streptococcus pneumoniae resistant to several common antibiotics, and some Gram-negative bacteria.[1]

A new drug application for iclaprim was filed with the U.S. Food and Drug Administration in March 2008,[3] and a marketing authorisation application (MAA) was accepted by the European Medicines Agency on August 21, 2008. Phase II clinical trials are being conducted to assess whether iclaprim can be taken by mouth as well as intravenously and whether it is effective for the treatment of hospital-acquired pneumonia.[4][5]

Iclaprim was granted fast track status by the FDA,[6] but approval of the drug was eventually declined in 2009[7] and no further development has taken place since then.

Iclaprim & NADPH bound to DHFR. PDB entry: 3FRA. The different amino acids are color coded.

References

  1. ↑ 1.0 1.1 Kohlhoff SA, Sharma R (September 2007). "Iclaprim". Expert Opin Investig Drugs 16 (9): 1441–8. doi:10.1517/13543784.16.9.1441. PMID 17714029.
  2. ↑ Kohlhoff, SA; Sharma, R (September 2007). "Iclaprim.". Expert Opinion on Investigational Drugs 16 (9): 1441–8. doi:10.1517/13543784.16.9.1441. PMID 17714029.
  3. ↑ 3.0 3.1 "Arpida Submits New Drug Application for Intravenous Iclaprim for Treatment of Skin Infections" (Press release). Reuters. March 19, 2008. Retrieved 2008-08-24.
  4. ↑ 4.0 4.1 "Arpida's iclaprim MAA Accepted for Review by EMEA" (Press release). PR Newswire. August 21, 2008. Retrieved 2008-08-24.
  5. ↑ Peppard, WJ; Schuenke, CD (February 2008). "Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor for the potential treatment of antibiotic-resistant staphylococcal infections". Current Opinion on Investigational Drugs 9 (2): 210–25. PMID 18246524.
  6. ↑ Morgan A, Cofer C, Stevens DL (March 2009). "Iclaprim: a novel dihydrofolate reductase inhibitor for skin and soft tissue infections". Future Microbiol 4 (2): 131–44. doi:10.2217/17460913.4.2.131. PMID 19257839.
  7. ↑ Arpida receives FDA complete response letter for Iclaprim

Further reading