Iclaprim (formerly known as AR-100 and RO-482622) is a novel diaminopyrimidine, and a selective inhibitor of dihydrofolate reductase which can inhibit the growth of S. aureus (MRSA) with an MIC90 of 0.06 μg/mL. It has shown potent, extended-spectrum in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and vancomycin-resistant S. aureus and macrolide-, quinolone- and trimethoprim-resistant strains. In addition, iclaprim has demonstrated activity against Streptococcus pneumoniae including penicillin-, erythromycin-, levofloxacin- and trimethoprim/sulfamethoxazole-resistant strains. Furthermore, in vitro activity has also been observed against Gram-negative bacteria and atypical bacteria. The pharmaco-kinetic profile of this agent reveals that iclaprim is available for intravenous and oral use, with good oral bioavailability. Phase II clinical trials have shown promise in its use for complicated skin and skin structure infections that are caused by methicillin-resistant S. aureus and two Phase III clinical trials have been recently completed for the same indication. Phase II trials evaluating the efficacy in respiratory infections are expected to start in 2007. At this early point in clinical development, the available reported data indicate potential for iclaprim as a new antibiotic for parenteral and oral treatment of complicated skin and skin structure infections.

Physicochemical Properties

Molecular Formula	C19H22N4O3
Molecular Weight	354.41
Exact Mass	354.169
Elemental Analysis	C, 64.39; H, 6.26; N, 15.81; O, 13.54
CAS #	192314-93-5
Related CAS #	Iclaprim-d6;1130072-57-9
PubChem CID	213043
Appearance	Solid powder
Density	1.3±0.1 g/cm3
Boiling Point	616.7±65.0 °C at 760 mmHg
Flash Point	326.8±34.3 °C
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.666
LogP	2.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	5
Heavy Atom Count	26
Complexity	515
Defined Atom Stereocenter Count	0
SMILES	NC1=NC=C(CC2=C3C=CC(C4CC4)OC3=C(OC)C(OC)=C2)C(N)=N1
InChi Key	HWJPWWYTGBZDEG-UHFFFAOYSA-N
InChi Code	InChI=1S/C19H22N4O3/c1-24-15-8-11(7-12-9-22-19(21)23-18(12)20)13-5-6-14(10-3-4-10)26-16(13)17(15)25-2/h5-6,8-10,14H,3-4,7H2,1-2H3,(H4,20,21,22,23)
Chemical Name	5-((2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl)pyrimidine-2,4-diamine
Synonyms	RO-482622; RO 482622; RO482622; AR-100; AR100; AR 100; RO-48-2622; AR-100.001
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Dihydrofolate
ln Vitro	Iclaprim inhibits the growth of S. aureus (MRSA) with an MIC90 of 0.06 μg/mL.
References	[1]. Iclaprim. Expert Opin Investig Drugs. 2007 Sep;16(9):1441-8. [2]. Bioorg Med Chem Lett. 2003 Dec 1;13(23):4217-21.
Additional Infomation	5-[(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl]pyrimidine-2,4-diamine is an aminopyrimidine that is 5-methylpyrimidine-2,4-diamine in which one of the hydrogens of the methyl group has been replaced by a 2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl group. It is an aminopyrimidine, a member of chromenes and a member of cyclopropanes. Drug Indication Investigated for use/treatment in bacterial infection, skin infections/disorders, obesity, liver disease, kidney disease, and pneumonia. Mechanism of Action Iclaprim is a novel diaminopyrimidine, and an inhibitor of dihydrofolate reductase, which has shown potent, extended-spectrum in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and vancomycin-resistant S. aureus and macrolide-, quinolone- and trimethoprim-resistant strains. In addition, iclaprim has demonstrated activity against Streptococcus pneumoniae including penicillin-, erythromycin-, levofloxacin- and trimethoprim/sulfamethoxazole-resistant strains.

Solubility Data

Solubility (In Vitro)

DMSO ： ~30 mg/mL (~84.65 mM）

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.8216 mL	14.1080 mL	28.2159 mL
	5 mM	0.5643 mL	2.8216 mL	5.6432 mL
	10 mM	0.2822 mL	1.4108 mL	2.8216 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.