Fatima Z. Basha

Angiotensin ii receptor antagonists

Blockade of the renin-angiotensin system began as a way of studying the pathogenesis of cardiovascular disease with specific pharmacological probes. Oral activity, achieved by shortening the original peptide structures, transformed the probes into therapeutic agents, the angiotensin-converting enzyme (ACE) inhibitors. However, ACE is a non-specific target for blocking the renin-angiotensin enzymatic cascade. The availability of orally active drugs turned ACE inhibition into a therapeutic breakthrough but more specific blockade always seemed desirable. This goal has now been achieved with the orally active angiotensin II receptor antagonists; six are on the market and more are under development. This new class of drugs is equal in efficacy to ACE inhibitors, at least in hypertensive patients. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality. If they do, these compounds might one day replace ACE inhibitors.Compounds are disclosed having the formula: ##STR1## The compounds of the invention are angiotensin II receptor antagonists.

A novel three carbon-amino grignard reagent: its use in an efficient pyrrolidine synthesis

Abstract A novel primary amino protected Grignard reagent has been developed; 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesium bromide 1a . Its usefulness is illustrated in the synthesis of 2-substituted pyrrolidines.

Methodology for the synthesis of the acyclic portions of verrucarins A and J

Abstract Syntheses of the acyclic chains of verrucarin A and J are described; the revised stereochemistry of verrucarin J is confirmed.

Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent α-2 antagonism with moderate NE uptake inhibition

Abstract ABT-200, (±)-(1′R*, 3R*)-3-phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylenedioxy-1′-naphthalenyl)methyl]pyrrolidine, ( 1a/b ) represents the first example of a new structural class of potent α-2 antagonists which possess the additional property of norepinephrine (NE) uptake inhibition. This profile of combined activities is expected to have utility in the treatment of depression.

Synthesis and In Vitro evaluation of fused ring heterocyle-containing angiotensin II antagonists.

Abstract Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.

Diastereoselection in the intramolecular diels-alder reaction of o-quinodimethanes.

Abstract An efficient diastereoselective synthesis of 2 is presented. A key feature is the intramolecular Diels-Alder reaction of o-quinodimethanes intermediates 3 derived from benzocyclobutenes 4 in which the exo-transition state is favored by incorporation of an amide functionality.