Pafuramidine | DB-289 | CAS#186953-56-0 | 837369-26-3 | antimalarial

MedKoo Cat#: 326798 | Name: Pafuramidine

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pafuramidine, also known as DB289, is an orally bioavailable prodrug of furamidine (DB75) which was developed for the treatment of human African trypanosomiasis. Pafuramidine is less toxic than previous diamidines such as pentamidine. To date, human trials suggest that pafuramidine is well tolerated overall and has clinical activity against Pneumocystis pneumonia. DB289 is a promising new antimalarial compound that could become an important component of new antimalarial combinations.

Chemical Structure

Pafuramidine

CAS#186953-56-0 (free base)

Theoretical Analysis

MedKoo Cat#: 326798

Name: Pafuramidine

CAS#: 186953-56-0 (free base)

Chemical Formula: C20H20N4O3

Exact Mass: 364.1535

Molecular Weight: 364.41

Elemental Analysis: C, 65.92; H, 5.53; N, 15.38; O, 13.17

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 550.00	2 Weeks
10mg	USD 950.00	2 Weeks

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Related CAS #

186953-56-0 (free base) 837369-26-3 (maleate)

Synonym

Pafuramidine; Pafuramidina; Pafuramidinum; DB289; DB-289; DB 289;

IUPAC/Chemical Name

N'-methoxy-4-[5-[4-[(Z)-N'-methoxycarbamimidoyl]phenyl]furan-2-yl]benzenecarboximidamide

InChi Key

UKOQVLAXCBRRGH-UHFFFAOYSA-N

InChi Code

InChI=1S/C20H20N4O3/c1-25-23-19(21)15-7-3-13(4-8-15)17-11-12-18(27-17)14-5-9-16(10-6-14)20(22)24-26-2/h3-12H,1-2H3,(H2,21,23)(H2,22,24)

SMILES Code

N/C(C1=CC=C(C2=CC=C(C3=CC=C(/C(N)=N/OC)C=C3)O2)C=C1)=N\OC

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Related CAS# 186953-56-0 (Pafuramidine) 837369-26-3 (Pafuramidine maleate)

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Pafuramidine (DB289) is an orally active prodrug of Furamidine (HY-110137A). Pafuramidine is a potent anti-parasitic agent, can be used to research trypanosomiasis, Pneumocystis pneumonia and malaria.

In vitro activity:

In the guinea pig ventricular myocytes, treatment with furamidine, a PRMT1-specific inhibitor, prolonged the action potential duration (APD). This study further show that this APD prolongation was attributable to IKs reduction. In HEK293T cells expressing human KCNQ1 and KCNE1, inhibiting PRMT1 via furamidine reduced IKs and concurrently decreased the arginine methylation of KCNQ1, a pore-forming α-subunit. Reference: J Cell Physiol. 2022 Jul;237(7):3069-3079. https://pubmed.ncbi.nlm.nih.gov/35580065/

In vivo activity:

The efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methlylamidoxime (pafuramidine, DB289), was tested in the vervet monkey (Chlorocebus [Cercopithecus] aethiops) model of sleeping sickness. In the groups treated in the early stage, 10 mg/kg of pafuramidine completely cured all three monkeys, whereas lower doses of 3 mg/kg and 1 mg/kg cured only one of three and zero of three monkeys, respectively. Treatment of late-stage infections resulted in cure rates of one of three (group 4) and zero of three (group 5) monkeys. These studies demonstrated that pafuramidine was orally active in monkeys with early-stage T. brucei rhodesiense infections at dose rates above 3 mg/kg for 5 days. Reference: Antimicrob Agents Chemother. 2009 Mar;53(3):953-7. https://pubmed.ncbi.nlm.nih.gov/19064893/

	Solvent	mg/mL	mM
Solubility
	DMSO	33.3	91.46

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 364.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. An X, Lee J, Kim GH, Kim HJ, Pyo HJ, Kwon I, Cho H. Modulation of IKs channel-PIP2 interaction by PRMT1 plays a critical role in the control of cardiac repolarization. J Cell Physiol. 2022 Jul;237(7):3069-3079. doi: 10.1002/jcp.30775. Epub 2022 May 17. PMID: 35580065; PMCID: PMC9543859. 2. Jenquin JR, Coonrod LA, Silverglate QA, Pellitier NA, Hale MA, Xia G, Nakamori M, Berglund JA. Furamidine Rescues Myotonic Dystrophy Type I Associated Mis-Splicing through Multiple Mechanisms. ACS Chem Biol. 2018 Sep 21;13(9):2708-2718. doi: 10.1021/acschembio.8b00646. Epub 2018 Aug 27. PMID: 30118588; PMCID: PMC6343479. 3. Mdachi RE, Thuita JK, Kagira JM, Ngotho JM, Murilla GA, Ndung'u JM, Tidwell RR, Hall JE, Brun R. Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration. Antimicrob Agents Chemother. 2009 Mar;53(3):953-7. doi: 10.1128/AAC.00831-08. Epub 2008 Dec 8. PMID: 19064893; PMCID: PMC2650535. 4. Thuita JK, Karanja SM, Wenzler T, Mdachi RE, Ngotho JM, Kagira JM, Tidwell R, Brun R. Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop. 2008 Oct;108(1):6-10. doi: 10.1016/j.actatropica.2008.07.006. Epub 2008 Aug 5. PMID: 18722336.

In vitro protocol:

In vivo protocol:

1. Mdachi RE, Thuita JK, Kagira JM, Ngotho JM, Murilla GA, Ndung'u JM, Tidwell RR, Hall JE, Brun R. Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration. Antimicrob Agents Chemother. 2009 Mar;53(3):953-7. doi: 10.1128/AAC.00831-08. Epub 2008 Dec 8. PMID: 19064893; PMCID: PMC2650535. 2. Thuita JK, Karanja SM, Wenzler T, Mdachi RE, Ngotho JM, Kagira JM, Tidwell R, Brun R. Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop. 2008 Oct;108(1):6-10. doi: 10.1016/j.actatropica.2008.07.006. Epub 2008 Aug 5. PMID: 18722336.

1: Dickie EA, Giordani F, Gould MK, Mäser P, Burri C, Mottram JC, Rao SPS, Barrett MP. New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story. Trop Med Infect Dis. 2020 Feb 19;5(1):29. doi: 10.3390/tropicalmed5010029. PMID: 32092897; PMCID: PMC7157223. 2: Jenquin JR, Yang H, Huigens RW 3rd, Nakamori M, Berglund JA. Combination Treatment of Erythromycin and Furamidine Provides Additive and Synergistic Rescue of Mis-Splicing in Myotonic Dystrophy Type 1 Models. ACS Pharmacol Transl Sci. 2019 Aug 9;2(4):247-263. doi: 10.1021/acsptsci.9b00020. Epub 2019 Jul 17. PMID: 31485578; PMCID: PMC6726129. 3: Wang Y, Li Y, Lu J, Qi H, Cheng I, Zhang H. Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro. Molecules. 2018 May 16;23(5):1195. doi: 10.3390/molecules23051195. PMID: 29772747; PMCID: PMC6100113. 4: Pohlig G, Bernhard SC, Blum J, Burri C, Mpanya A, Lubaki JP, Mpoto AM, Munungu BF, N'tombe PM, Deo GK, Mutantu PN, Kuikumbi FM, Mintwo AF, Munungi AK, Dala A, Macharia S, Bilenge CM, Mesu VK, Franco JR, Dituvanga ND, Tidwell RR, Olson CA. Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator- Controlled, International Phase 3 Clinical Trial. PLoS Negl Trop Dis. 2016 Feb 16;10(2):e0004363. doi: 10.1371/journal.pntd.0004363. PMID: 26882015; PMCID: PMC4755561. 5: Burri C, Yeramian PD, Allen JL, Merolle A, Serge KK, Mpanya A, Lutumba P, Mesu VK, Bilenge CM, Lubaki JP, Mpoto AM, Thompson M, Munungu BF, Manuel F, Josenando T, Bernhard SC, Olson CA, Blum J, Tidwell RR, Pohlig G. Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies. PLoS Negl Trop Dis. 2016 Feb 16;10(2):e0004362. doi: 10.1371/journal.pntd.0004362. PMID: 26881924; PMCID: PMC4755713. 6: Michaels S, Wang MZ. The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics. Drug Metab Dispos. 2014 Aug;42(8):1241-51. doi: 10.1124/dmd.114.058040. Epub 2014 May 9. PMID: 24816681; PMCID: PMC4109210. 7: Harrill AH, Desmet KD, Wolf KK, Bridges AS, Eaddy JS, Kurtz CL, Hall JE, Paine MF, Tidwell RR, Watkins PB. A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models. Toxicol Sci. 2012 Dec;130(2):416-26. doi: 10.1093/toxsci/kfs238. Epub 2012 Aug 31. PMID: 22940726; PMCID: PMC3498743. 8: Thuita JK, Wang MZ, Kagira JM, Denton CL, Paine MF, Mdachi RE, Murilla GA, Ching S, Boykin DW, Tidwell RR, Hall JE, Brun R. Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis. PLoS Negl Trop Dis. 2012;6(7):e1734. doi: 10.1371/journal.pntd.0001734. Epub 2012 Jul 24. PMID: 22848769; PMCID: PMC3404106. 9: Yan GZ, Generaux CN, Yoon M, Goldsmith RB, Tidwell RR, Hall JE, Olson CA, Clewell HJ, Brouwer KL, Paine MF. A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair. Drug Metab Dispos. 2012 Jan;40(1):6-17. doi: 10.1124/dmd.111.040063. Epub 2011 Sep 27. PMID: 21953913; PMCID: PMC3250045. 10: Batista Dda G, Batista MM, de Oliveira GM, Britto CC, Rodrigues AC, Stephens CE, Boykin DW, Soeiro Mde N. Combined treatment of heterocyclic analogues and benznidazole upon Trypanosoma cruzi in vivo. PLoS One. 2011;6(7):e22155. doi: 10.1371/journal.pone.0022155. Epub 2011 Jul 26. PMID: 21814568; PMCID: PMC3144210. 11: Yan GZ, Brouwer KL, Pollack GM, Wang MZ, Tidwell RR, Hall JE, Paine MF. Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models. J Pharmacol Exp Ther. 2011 May;337(2):503-12. doi: 10.1124/jpet.110.177220. Epub 2011 Feb 14. PMID: 21320872; PMCID: PMC3083101. 12: Barrett MP. Potential new drugs for human African trypanosomiasis: some progress at last. Curr Opin Infect Dis. 2010 Dec;23(6):603-8. doi: 10.1097/QCO.0b013e32833f9fd0. PMID: 20844428. 13: Paine MF, Wang MZ, Generaux CN, Boykin DW, Wilson WD, De Koning HP, Olson CA, Pohlig G, Burri C, Brun R, Murilla GA, Thuita JK, Barrett MP, Tidwell RR. Diamidines for human African trypanosomiasis. Curr Opin Investig Drugs. 2010 Aug;11(8):876-83. PMID: 20721830. 14: Goldsmith RB, Gray DR, Yan Z, Generaux CN, Tidwell RR, Reisner HM. Application of monoclonal antibodies to measure metabolism of an anti- trypanosomal compound in vitro and in vivo. J Clin Lab Anal. 2010;24(3):187-94. doi: 10.1002/jcla.20380. Erratum in: J Clin Lab Anal. 2011;25(4):309. PMID: 20486201; PMCID: PMC6647651. 15: Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R. New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289. Antimicrob Agents Chemother. 2009 Oct;53(10):4185-92. doi: 10.1128/AAC.00225-09. Epub 2009 Jul 20. PMID: 19620327; PMCID: PMC2764217. 16: Nyunt MM, Hendrix CW, Bakshi RP, Kumar N, Shapiro TA. Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2009 Apr;80(4):528-35. PMID: 19346370; PMCID: PMC2763313. 17: Mdachi RE, Thuita JK, Kagira JM, Ngotho JM, Murilla GA, Ndung'u JM, Tidwell RR, Hall JE, Brun R. Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration. Antimicrob Agents Chemother. 2009 Mar;53(3):953-7. doi: 10.1128/AAC.00831-08. Epub 2008 Dec 8. PMID: 19064893; PMCID: PMC2650535. 18: Thuita JK, Karanja SM, Wenzler T, Mdachi RE, Ngotho JM, Kagira JM, Tidwell R, Brun R. Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop. 2008 Oct;108(1):6-10. doi: 10.1016/j.actatropica.2008.07.006. Epub 2008 Aug 5. PMID: 18722336. 19: Purfield AE, Tidwell RR, Meshnick SR. Interactions of DB75, a novel antimalarial agent, with other antimalarial drugs in vitro. Antimicrob Agents Chemother. 2008 Jun;52(6):2253-5. doi: 10.1128/AAC.01536-07. Epub 2008 Mar 24. PMID: 18362196; PMCID: PMC2415804. 20: Chen D, Marsh R, Aberg JA. Pafuramidine for Pneumocystis jiroveci pneumonia in HIV-infected individuals. Expert Rev Anti Infect Ther. 2007 Dec;5(6):921-8. doi: 10.1586/14787210.5.6.921. PMID: 18039076.