Robert Louis Rosati

Effects of CP-336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models.

We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-α with a half-inhibition concentration of 1.5 nm, which is similar to that seen with estradiol (4.8 nm). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 μg/kg·day, unlike 17α-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (po) with CP-336,156 at 10 or 100 μg/kg·day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 μg/kg·day after 4 weeks. At...

Discovery of Inhibitors of Human Renin with High Oral Bioavailability

Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren (22). Modification of physical properties led to the synthesis of aminopiperidine 30, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor 34. Its bioactive monomethylamine metabolite (35, CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates.

Synthesis of α-hydroxy statine through a facially selective osmylation of a chiral α-amido crotonate

Abstract α-hydroxy statine 5 was synthesized by osmylation of amido crotonate 6 and incorporated into peptide framework 9, resulting in an active renin inhibitor; predicted stereochemical preferences for renin inhibition were confirmed by x-ray analysis and biochemical determinations. The facial selectivity of the osmylation is consistent with the Vedejs model.

CP-71,362, an unusually potent inhibitor of rat and dog renin

Abstract CP-71,362 (Boc-Phe-His-hexahydroPhe[OH]Leu-Lys-Phe) has been identified as the most potent inhibitor of rat plasma renin (IC50 = 3 nM) and dog plasma renin (IC50 = 3 pM) to date and thus can be used as an important experimental tool in the study of the renin angiotensin system in these established hypertensive models.

X-ray analysis of a difluorostatone renin inhibitor bound as the tetrahedral hydrate to the aspartic protease endothiapepsin.

In this study we report the X-ray analysis of a complex between the aspartic protease endothiapepsin (EC 3.4.23.6) and an inhibitor bound as a carbonyl hydrate (gem-diol) to the catalytic aspartates of this enzyme, in a manner closely resembling the putative tetrahedral intermediate in proteolytic cleavage of the peptide bond.1 This study was undertaken in order to obtain a closer model of the interactions stabilizing this intermediate than those used in previous analyses, which were based on X-ray crystallographic data obtained from inhibitors lacking one or both of the hydroxyl residues of this species.2,3

Synthesis of (1-S) and (1-R) cis 2-methylcyclopentanols through lipase mediated resolution

Abstract The lipase catalyzed enantioselective transacylation of (±) cis -2-methylcyclopentanol is described.