Richard Lee Simon

Angiotensin ii antagonists

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Synthesis and structure-activity relationships of benzophenones as inhibitors of cathepsin D

Abstract Non peptide inhibitors of cathepsin D, an aspartyl protease that has been implicated in many disease states including Alzheimers disease, were prepared and evaluated. The most potent inhibitor of cathepsin D in this series was found to be (Z)-5-[[4-(4-benzoyl-3-hydroxy-2-propylphenoxy) methylphenyl]methylene]-2-thioxo-4-thiazolidinone ( 3f , IC 50 = 210 nM).

A novel class of 5-HT2a receptor antagonists: Aryl aminoguanidines

Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with 125I DOI on human 5-HT2A and 5-HT2C receptors and with 3H-5-HT on human 5-HT2B receptors demonstrated that, LY314228, and LY320954 displayed some selectivity for the 5-HT2A receptor. When compared to binding at other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater affinity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater at the 5-HT2C site. LY320954 displayed similar preference for 5-HT2A sites. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED50s of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respectively). These studies offer evidence for a novel class of pharmacophores for the 5-HT2 receptor family which show greater relative affinities for the 5-HT2A receptor subclass.

Chiral recognition of the angiotensin II (AT1) receptor by a highly potent phenoxyproline octanoamide

Abstract The synthesis and in vitro biological evaluation of a novel series of diastereomeric phenoxyproline octanoamides ( 3–h ) as angiotensin II (AT 1 ) receptor antagonists are reported.