Sch-42495 racemate

Sch-42495 racemate is the racemate of Sch-42495. Sch-42495 is a novel neutral metalloendopeptidase (NEP) inhibitor. Sch-42495 is the orally active ethylester prodrug of SCH 42354.

SCH 42354 selectively inhibits hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nM, respectively) in vitro[1].

Plasma levels of exogenous atrial natriuretic factor (ANF) are augmented and ANF clearance from plasma is delayed by oral Sch-42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats are higher in Sch-42495-treated rats. Diuretic and natriuretic effects of ANF are increased in rats treated with Sch-42495. In Dahl-S hypertensive rats, Sch-42495 (1 to 10 mg/kg orally) produces falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity is observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of Sch-42495 significantly decreases cardiac output and does not lower systemic vascular resistance, a profile similar to that of ANF[1]. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks are injected with either Streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either Captopril (25 mg/kg BID), Sch-42495 (30 mg/kg BID), S21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR is also allocated to receive the combination of Sch-42495 (30 mg/kg BID) and Captopril (25 mg/kg BID). The degree of renal NEP inhibition is determined by autoradiography, and plasma renin activity (PRA) is determined by radioimmunoassay. In nondiabetic SHR, S21402 and Captopril are equally effective. Relative heart weight decreases in parallel to the changes in blood pressure. Renal NEP is clearly inhibited (70% to 92%; P

[1]. Watkins RW, et al. Atrial natriuretic factor potentiating and hemodynamic effects of SCH 42495, a new, neutral metalloendopeptidase inhibitor. Am J Hypertens. 1993 May;6(5 Pt 1):357-68. [2]. Tikkanen T, et al. Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. Hypertension. 1998 Oct;32(4):778-85.