Tamara Dejneka

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

A general synthesis of dioxolenone prodrug moieties

Abstract A general method for the synthesis of dioxolenone prodrug moieties from appropriately substituted β-ketoesters is described. This novel and versatile sequence allows for the synthesis of alkyl- or aryl-substituted dioxolenone alcohols 8 or bromides 9 . Coupling of the bromides 9 to prepare bis-dioxolenone phosphonate prodrug esters is also presented.

Orally active prodrugs of quinoline-4-carboxylic acid angiotensin II receptor antagonists

Abstract Prodrug derivatization of a potent quinoline-4-carboxylic acid angiotensin II receptor antagonist was Undertaken as an approach to achieve improved oral activity. A dioxolenone carboxylic ester and an alkylated tetrazole prodrug both showed greater oral antihypertensive acivity in the salt-deplete spontaneously hypertensive rat and increased oral bioavailability relative to the parent compound.

1,4-substituted indoles: a potent and selective class of angiostensin II receptor antagonists

The syntheses and pharmacological activity of a series of 1,4-substituted indoles which function as nonpeptidic antagonists of the angiotensin II (AII) receptor are described. Compounds in this series are orally active and demonstrate long lasting antihypertensive activity.

Quinoline-4-carboxylic acids as angiotensin II receptor antagonists

Abstract We have synthesized a series of quinoline-4-carboxylic acids that are potent antagonists of the angiotensin II receptor. They show high receptor binding affinities and functional antagonism in rabbit aortic strips. They are also effective in blocking the hypertensive effects of AII in vivo

Diol sulfonamides: A potent and novel class of inhibitors of human renin

Abstract The syntheses and pharmacological activity of a series of diol sulfonamides which function as inhibitors of human renin are described. The most potent compound in this series, compound 20 (SQ 33,800 ), is a subnanomolar inhibitor of human renin (IC 50 = 0.35 × 10 −9 M).