Warfarin structure

N. Thuaud, B. Sebille, A. Deratani, and G. Lelievre, Retention behavior and chiral recognition of /3-cyclodextrin derivative polymer adsorbed on silica for warfarin, structurally related compounds and Dns-amino acids, J. Chromatogr., 555 53 (1991). 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Warfarin and the second-generation superwarfarins are ARs that have a structural resemblance to dicoumarol and vitamin K. They act as vitamin K antagonists, thereby retarding or stopping the carboxylation of clotting proteins in the hepatic endoplasmic reticulum. The buildup of nonfunctional, undercarboxylated clotting proteins in the blood leads eventually to death by hemorrhaging. 

Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 2003 424 464-8. 

Dong quai No demonstrated efficacy Not recommended Structurally similar to coumarins—avoid with warfarin because INR can increase... 

The effect of relative humidity and temperature on the physical and structural properties of the 1 1 isopropanol solvatomorph of warfarin has been studied [58], Below the critical relative humidity of 60-68% the solid is not hygroscopic, but becomes deliquescent at higher values of relative humidity without exchange of water for isopropanol. Storage of the solvate-morph at elevated temperatures causes formation of an amorphous solid owing to loss of isopropanol, which may proceed through an intermediate crystalline phase. 

FIGURE 4.11 Structures of the CYP2C9 substrates, warfarin, tolbutamide, (S (-flurbiprofen, and diclofenac, and their metabolites. 

Figure 15.15 Different forms of vitamin K and the structure of an antagonist, warfarin.

Fig. 14.8 Experimental ligand interactions with cytochrome P450 2C family. (A) X-ray structure ofthe sulfaphenazole derivate DMZ in rabbit CYP2C5 at 2.3 A resolution (PDB 1 N5B) from Wester et al. [191]. Only one ofthe two-ligand orientations for DMZ in accord with electron density is shown placing the benzylic methyl group in a 4.4 A distance to the heme iron. (B) X-ray structure of S-warfarin in human CYP2C9 at 2.55 A resolution (PDB 10G5) from Williams et al. [192]. The substrate is situated in a predominantly hydrophobic pocket. This binding mode places the 6- and 7-hydroxylation sites 10 A from the iron (arrow).

Twine, S., East, M., and Curry, S. Crystal structure analysis of warfarin binding to human serum albumin. Anatomy of dmg site I. /. Biol. Chem. 

Because rodent populations world-wide were becoming resistant to the widely used Warfarin-type anticoagulant poisons, a search was initiated to find a rodenticide with a different mode of action one that would be effective against these resistant rodents. This search led to the discovery of the toxic nature of a family of diphenyl amines which act as uncouplers of oxidative phosphorylation. A structure-activity relationship (SAR) study was undertaken to choose a derivative that would be both poisonous to rodents but still readily consumed by them. This approach led to the discovery of bromethalin,... 

The discovery of the anticoagulant properties of dicoumarin (j ) led to the development of the more potent anticoagulant warfarin (2), (Structure 1). The subsequent discovery that the anticoagulants can be successfully used as multiple dose... 

Very rapidly, a number of other anticoagulants, including the indanediones (4), (Structure 2), were developed as rodenticides. Warfarin first came into wide usage as a rodenticide in 1950 and virtually supplanted all other materials then in use. In the case of all these early materials, multiple bait applications were needed to control rodent populations which, while making the materials safer to use than the available acute poisons, curtailed their use in underdeveloped and less affluent countries because of the large quantities of bait that must be placed to destroy the populations of rodents. 

A bismuth-catalyzed alkylation of warfarins has not been described, although a bismuth-mediated synthesis of the coumarin core structure 21 starting from phenols 19 and ethyl acetoacetate 20 is known (Scheme 17) [51]. The synthesis of coumarins proceeds in the same way as the above-described indene synthesis. The initial reaction of phenol 19 and ethyl acetoacetate 20 leads to the ester. 

Scheme 16 3-Alkylated 4-hydroxycoumarins the core structure for various warfarin derivatives...

This study also suggests that molecular size and structure play a role in this interaction. The binding behaviors of dextrin oligomers for four different pharmaceuticals (ibuprofen, ketoprofen, furosemide, and warfarin) were observed under the same experimental conditions. Ibuprofen and ketoprofen, two compounds that are similar in chemical structure and pharmaceutical use, showed obvious differences in interaction patterns (Fig. 13A and B). Ketoprofen, having an extra aromatic ring, required an octa-saccharide (DP = 8) for binding, whereas ibuprofen required a heptasac-... 

Ciprofloxacin (Cipro, Cipro XR, Proquin XR) [Antibiotic/ Fluoroquinolone] Uses Rx lower resp tract, sinuses, skin skin structure, bone/joints, urinary tract Infxns including prostatitis Action Quinolone antibiotic DNA gyrase Dose Adults. 250-750 mg PO ql2h XR 500-1000 mg PO q24h or 200-400 mg IV ql2h in renal impair Caution [C, /-] Children <18 y Contra Component sensitivity Disp Tabs, susp, inj SE Restlessness, N/V/D, rash, ruptured tendons, T LFTs Interactions T Effects Wf probenecid T effects OF diazepam, theophylline, caffeine, metoprolol, propranolol, phenytoin, warfarin effects W/ antacids, didanosine, Fe salts. Mg, sucralfate, Na bicarbonate,... 

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