Novel 5-HT3 receptor antagonists and methods of use
AssigneeARYx Therapeutics, Inc.
InventorsXiaming Zhang, Jurg R. Pfister, Cyrus Becker, Pascal Druzgala
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Abstract
The subject invention provides useful and novel 5-HT3 antagonists. The subject invention also provides methods for synthesizing the compounds of invention. The invention also provides methods for the treatment of irritable bowel syndrome and other such conditions.
Claims23
A 5-HT3 receptor antagonist having at least one characteristic chosen from the group consisting of:
- 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 a 5-HT3 receptor antagonist having at least one characteristic chosen from the group consisting of:
- 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 further comprises a pharmaceutical carrier.
The composition, according to claim 10, comprising a compound having the following structure:
- 8
- X=N, or CH
- R=lower alkyl optionally substituted with OH or NH2.
A method for blocking 5-HT3 activity in a patient in need of such treatment wherein said method comprises administering to said patient a 5-HT3 blocking 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.