DPC-423 HCl | 292135-59-2 (HCl) | Factor Xa Inhibitor

MedKoo Cat#: 528203 | Name: DPC-423 HCl

Description:

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

DPC-423 is a factor Xa inhibitor potentially for the treatment of thrombosis. In vivo and in vitro studies with the synthetic oxime intermediate from DPC-423 showed an adduct identical to the one isolated from the bile of rats dosed with DPC-423. This supported the intermediacy of an aldoxime as a precursor to the GSH adducts. It is postulated that the benzylamine moiety of DPC-423 (and its analogues) is oxidized to a hydroxylamine, which is subsequently converted to a nitroso intermediate. Subsequent rearrangement of the nitroso leads to an aldoxime which in turn is metabolized by P450 to a reactive intermediate. The formation of oxime from DPC-423 (and its analogues) was found to be mediated by rat CYP 3A1/2, which were also responsible for converting the oxime to the GSH trappable reactive intermediate.

Chemical Structure

DPC-423 HCl

CAS#292135-59-2 (HCl)

Theoretical Analysis

MedKoo Cat#: 528203

Name: DPC-423 HCl

CAS#: 292135-59-2 (HCl)

Chemical Formula: C25H21ClF4N4O3S

Exact Mass: 0.0000

Molecular Weight: 568.97

Elemental Analysis: C, 52.78; H, 3.72; Cl, 6.23; F, 13.36; N, 9.85; O, 8.44; S, 5.63

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Related CAS #

292135-59-2 (HCl); 209957-47-1 (free)

Synonym

DPC-423; DPC 423; DPC423; DPC-423 HCl; DPC-423 hydrochloride;

IUPAC/Chemical Name

1-(3-(aminomethyl)phenyl)-N-(3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide hydrochloride

InChi Key

LJBVKRYJJZQKGE-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H20F4N4O3S.ClH/c1-37(35,36)22-8-3-2-7-18(22)16-9-10-20(19(26)12-16)31-24(34)21-13-23(25(27,28)29)32-33(21)17-6-4-5-15(11-17)14-30;/h2-13H,14,30H2,1H3,(H,31,34);1H

SMILES Code

O=C(C1=CC(C(F)(F)F)=NN1C2=CC=CC(CN)=C2)NC3=CC=C(C4=CC=CC=C4S(=O)(C)=O)C=C3F.[H]Cl

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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

DPC-423 is a factor Xa inhibitor potentially for the treatment of thrombosis.

In vitro activity:

Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development. Reference: J Med Chem. 2001 Feb 15;44(4):566-78. https://pubmed.ncbi.nlm.nih.gov/11170646/

In vivo activity:

DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity in rabbits. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis. Reference: J Pharmacol Exp Ther. 2002 Dec;303(3):993-1000. https://pubmed.ncbi.nlm.nih.gov/12438519/

Preparing Stock Solutions

The following data is based on the product molecular weight 568.97 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. Mutlib AE, Chen SY, Espina RJ, Shockcor J, Prakash SR, Gan LS. P450-mediated metabolism of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)- [1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole- 5-carboxamide (DPC 423) and its analogues to aldoximes. Characterization of glutathione conjugates of postulated intermediates derived from aldoximes. Chem Res Toxicol. 2002 Jan;15(1):63-75. doi: 10.1021/tx0101189. PMID: 11800598. 2. Pinto DJ, Orwat MJ, Wang S, Fevig JM, Quan ML, Amparo E, Cacciola J, Rossi KA, Alexander RS, Smallwood AM, Luettgen JM, Liang L, Aungst BJ, Wright MR, Knabb RM, Wong PC, Wexler RR, Lam PY. Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem. 2001 Feb 15;44(4):566-78. doi: 10.1021/jm000409z. PMID: 11170646. 3. Chi C, Liang L, Padovani P, Unger S. Development and validation of a liquid chromatography-mass spectrometric method for the determination of DPC 423, an antithrombotic agent, in rat and dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jan 5;783(1):163-72. doi: 10.1016/s1570-0232(02)00633-5. PMID: 12450535. 4. Wong PC, Crain EJ, Watson CA, Zaspel AM, Wright MR, Lam PY, Pinto DJ, Wexler RR, Knabb RM. Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits. J Pharmacol Exp Ther. 2002 Dec;303(3):993-1000. doi: 10.1124/jpet.102.040089. PMID: 12438519.

In vitro protocol:

In vivo protocol:

1. Chi C, Liang L, Padovani P, Unger S. Development and validation of a liquid chromatography-mass spectrometric method for the determination of DPC 423, an antithrombotic agent, in rat and dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jan 5;783(1):163-72. doi: 10.1016/s1570-0232(02)00633-5. PMID: 12450535. 2. Wong PC, Crain EJ, Watson CA, Zaspel AM, Wright MR, Lam PY, Pinto DJ, Wexler RR, Knabb RM. Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits. J Pharmacol Exp Ther. 2002 Dec;303(3):993-1000. doi: 10.1124/jpet.102.040089. PMID: 12438519.

1: Taglialatela M. DPC-423 Bristol-Myers Squibb. Curr Opin Investig Drugs. 2002 Feb;3(2):252-4. Review. PubMed PMID: 12020055. 2: Mutlib A, Shockcor J, Chen SY, Espina R, Lin J, Graciani N, Prakash S, Gan LS. Formation of unusual glutamate conjugates of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and its analogs: the role of gamma-glutamyltranspeptidase in the biotransformation of benzylamines. Drug Metab Dispos. 2001 Oct;29(10):1296-306. PubMed PMID: 11560873. 3: Mutlib AE, Chen SY, Espina RJ, Shockcor J, Prakash SR, Gan LS. P450-mediated metabolism of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)- [1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole- 5-carboxamide (DPC 423) and its analogues to aldoximes. Characterization of glutathione conjugates of postulated intermediates derived from aldoximes. Chem Res Toxicol. 2002 Jan;15(1):63-75. PubMed PMID: 11800598. 4: Quan ML, Wexler RR. The design and synthesis of noncovalent factor Xa inhibitors. Curr Top Med Chem. 2001 Jun;1(2):137-49. Review. PubMed PMID: 11899249. 5: Mutlib AE, Shockcor J, Chen SY, Espina RJ, Pinto DJ, Orwat MJ, Prakash SR, Gan LS. Disposition of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'- (methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (DPC 423) by novel metabolic pathways. Characterization of unusual metabolites by liquid chromatography/mass spectrometry and NMR. Chem Res Toxicol. 2002 Jan;15(1):48-62. PubMed PMID: 11800597. 6: Chi C, Liang L, Padovani P, Unger S. Development and validation of a liquid chromatography-mass spectrometric method for the determination of DPC 423, an antithrombotic agent, in rat and dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jan 5;783(1):163-72. PubMed PMID: 12450535. 7: Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic. Curr Top Med Chem. 2005;5(16):1677-95. Review. PubMed PMID: 16375748.