Materials and methods for treating coagulation disorders
AssigneeARYx Therapeutics, Inc.
InventorsPascal Druzgala, Xiaoming Zhang, Jurg Pfister
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Abstract
This invention is drawn to compounds which are more easily metabolized by the metabolic drug detoxification systems. Particularly, warfarin analogs which have been designed to include esters within the structure of the compounds are taught. The invention teaches methods of reducing the toxicity of drugs comprising the introduction of ester groups into drugs during the synthesis of the drug. This invention is also drawn to methods of treating coagulation disorders comprising the administration of compounds which have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester containing warfarin, analogs are also taught.
Claims28
An anticoagulant compound having at least one of the following characteristics:
- a. the compound is metabolized both by CYP450 and by a non-oxidative metabolic enzyme or system of enzymes;
- b. the compound has a short (up to four (4) hours) non-oxidative metabolic half-life;
- c. the compound contains a hydrolysable bond that can be cleaved non-oxidatively by hydrolytic enzymes;
- d. the primary metabolites of the compound result from the non-oxidative metabolism of the compound;
- e. the primary metabolites are soluble in water at physiological pH;
- f. the primary metabolites have negligible inhibitory activity at the IKR (HERG) channel at normal therapeutic concentration of the parent drug in plasma;
- g. the compound, as well as the metabolites thereof, does not cause metabolic DDI when co-administered with other drugs;
- and
- h. the compound, as well as metabolites thereof, does not elevate LFT values when administered alone.
A pharmaceutical composition comprising an anticoagulant compound having at least one of the following characteristics:
- a. the compound is metabolized both by CYP450 and by a non-oxidative metabolic enzyme or system of enzymes;
- b. the compound has a short (up to four (4) hours) non-oxidative metabolic half-life;
- c. the compound contains a hydrolysable bond that can be cleaved non-oxidatively by hydrolytic enzymes;
- d. the primary metabolites of the compound result from the non-oxidative metabolism of the compound;
- e. the primary metabolites are soluble in water at physiological pH;
- f. the primary metabolites have negligible inhibitory activity at the IKR (HERG) channel at normal therapeutic concentration of the parent drug in plasma;
- g. the compound, as well as the metabolites thereof, does not cause metabolic DDI when co-administered with other drugs;
- and
- h. the compound, as well as metabolites thereof, does not elevate LFT values when administered alone;
- wherein said composition comprises a pharmaceutical carrier.
A method for providing anticoagulant activity to a patient in need of such activity wherein said method comprises administering to said patient an anticoagulant compound having at least one of the following characteristics:
- a. the compound is metabolized both by CYP450 and by a non-oxidative metabolic enzyme or system of enzymes;
- b. the compound has a short (up to four (4) hours) non-oxidative metabolic half-life;
- c. the compound contains a hydrolysable bond that can be cleaved non-oxidatively by hydrolytic enzymes;
- d. the primary metabolites of the compound result from the non-oxidative metabolism of the compound;
- e. the primary metabolites are soluble in water at physiological pH;
- f. the primary metabolites have negligible inhibitory activity at the IKR (HERG) channel at normal therapeutic concentration of the parent drug in plasma;
- g. the compound, as well as the metabolites thereof, does not cause metabolic DDI when co-administered with other drugs;
- and
- h. the compound, as well as metabolites thereof, does not elevate LFT values when administered alone.
Dependencies are inferred from the claim text.