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Pyrido[2,3-d]pyrimidine angiotensin II antagonists
J W Ellingboe1, M Antane, T T Nguyen
1Wyeth-Ayerst Research, Division of Exploratory Chemistry, Princeton, New Jersey 08543-8000.
Journal of Medicinal Chemistry
|February 18, 1994
Summary
New pyridopyrimidine compounds effectively block angiotensin II (A II) receptors. Compound 4a demonstrates potent oral bioavailability and efficacy in treating high renin hypertension.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cardiovascular Research
Background:
- Angiotensin II (A II) plays a crucial role in regulating blood pressure.
- Developing potent and selective A II antagonists is a key strategy for hypertension treatment.
- Pyrido[2,3-d]pyrimidine derivatives have emerged as a promising scaffold for A II antagonists.
Purpose of the Study:
- To synthesize and evaluate novel pyridopyrimidine derivatives as angiotensin II antagonists.
- To identify compounds with high affinity for the AT1 receptor and potent A II antagonism.
- To assess the in vivo efficacy and pharmacokinetic properties of lead compounds in hypertensive rat models.
Main Methods:
- Synthesis of a series of pyridopyrimidine compounds featuring a biphenylyltetrazole pharmacophore.
- AT1 receptor binding assays to determine antagonist affinity.
- In vivo studies in anesthetized, ganglion-blocked rats to measure A II pressor response.
- Evaluation of compound 4a in Goldblatt (2K-1C) hypertensive rats to assess oral bioavailability and efficacy.
Main Results:
- Compounds with biphenylyltetrazole and small alkyl groups at positions 2 and 4 of the pyridopyrimidine ring showed the highest potency.
- Compound 4a exhibited potent binding in the AT1 receptor assay and significant efficacy in blocking the A II pressor response.
- In Goldblatt rats, compound 4a demonstrated oral bioavailability and was efficacious in a high renin hypertension model.
Conclusions:
- The synthesized pyridopyrimidine derivatives, particularly those with a biphenylyltetrazole moiety, are potent angiotensin II antagonists.
- Compound 4a represents a highly promising candidate for the treatment of hypertension, especially high renin forms, due to its efficacy and oral bioavailability.