Kenneth J. Fitch

Potent dual antagonists of endothelin and angiotensin II receptors derived from α-phenoxyphenylacetic acids (Part III)

Abstract Screening a collection of α-phenoxyphenylacetic acid derived angiotensin II antagonists identified weak actives in an endothelin receptor binding assay. Synthetic modification of one of these leads has provided L-746,072 (13), a highly potent dual antagonist of angiotensin II and endothelin receptors.

Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist

L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.

Synthesis of new imidazo[1,2-b]pyridazine isosteres of potent imidazo[4,5-b]pyridine angiotensin II antagonists

Abstract The synthesis of a new class of angiotensin II receptor antagonists bearing a substituted imidazo[1,2-b]pyridazine moiety, and the evaluation of these compounds as isosteric replacements for potent imidazo[4,5-b]pyridine based antagonists is presented.

AT1 selective angiotensin II antagonists with phenoxyphenylacetic acid as a biphenyl replacement part I

Abstract A series of nonpeptidic AT1 selective angiotensin II (AII) antagonists containing a phenoxyphenylacetic acid element as a biphenyl tetrazole replacement have been identified. This series yielded compound 20 which exhibited binding affinities of AT1 = 16 nM; AT2 = 22 μM and demonstrated modest in vivo duration in blockade of AII pressor response in conscious rats after either i.v. or p.o. administration.

α-Phenoxyphenylacetic acid derived angiotensin II antagonists with low nanomolar AT1/AT2 receptor subtype affinity (Part II)

Abstract Directed synthesis and pharmacological evaluation in a recently described class of α-phenoxyphenylacetic acid bearing angiotensin II (AII) receptor antagonists has afforded further potent AT 1 -selective AII antagonists. Substitution in the central aromatic ring significantly increases AT 2 receptor affinity such that the n -propyl derivative 7g displayed low nanomolar potency at both AT 1 and AT 2 receptor subtypes.

ACIDIC PHENOLS: A NEW CLASS OF POTENT NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS

Abstract A series of imidazo[4,5-b]pyridine-based acidic phenols (Table 1,2) and biphenyl ethers (Table 3) are exemplified as novel non-peptide AII receptor antagonists. 0,0′-substituents which affect the acidity of the phenolic portion dramatically impact the activity of the compounds. The most potent antagonist in this series (Compound 13 , IC50 = 5 nM, rabbit aorta) exhibited good in vivo potency after both iv and oral administration to conscious rats.