Ciprokiren (Ro 44-9375). A renin inhibitor with increasing effects on chronic treatment.

Abstract

The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IQ,, of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IQo, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with T he renin-angiotensin system (RAS) is involved in the regulation of blood pressure and fluid homeostasis. It generates its effector hormone angiotensin II (Ang II) in two steps. In a first step, renin cleaves its protein substrate angiotensinogen to release the biologically inactive decapeptide Ang I. In a second step, Ang I is further cleaved to the octapeptide Ang II by angiotensin-converting enzyme (ACE). Ang II finally interacts with at least two different receptor subtypes, AT] and AT 2 . Whereas AT, seems to be responsible for most of the known functions of Ang II, the function of AT 2 is unclear at present.

Sodium Dithionite‐Mediated Decarboxylative Sulfonylation: Facile Access to Tertiary Sulfones

“…Tertiary sulfones are among the most important motifs in pharmaceuticals due to their excellent effects on the rate of drug metabolism. A selection of well‐known tertiary sulfones as inhibitors is shown in Scheme A . In addition, a sulfone, as a bioisostere of the carboxylic motif, can be exchanged for a carboxyl group in a straightforward manner, which is of great significance for drug discovery.…”

“…A selection of well-known tertiary sulfones as inhibitors is shown in Scheme 1 A. [3][4][5][6][7] In addition, a sulfone, as a bioisostere of the carboxylic motif, can be exchanged for a carboxyl group in a straightforward manner, which is of great significance for drug discovery. Since DABSO [DABCO•-(SO 2 ) 2 ] was first applied as a sulfur dioxide surrogate, [8] strategies for the direct insertion of SO 2 into two coupling partners has been intensively studied due to the step economy and oxidative economy of such strategies for sulfone synthesis.…”

“…A base is necessary to capture superfluous SO 2 releasing from inorganic salt in the current transformation. Various bases were further tested for their abilities to activate the masking group of the inorganic sulfur salts, and DIPEA was found to provide the best results (55 % yield, Table 1, entries [3][4][5][6][7][8]. The addition of zinc chloride was found to facilitate product formation (60 % yield) since it favors decarboxylation via chelation with the carbonyls (Table 1, entries [9][10][11].…”

Potential side effects of renin inhibitors – mechanisms based on comparison with other renin–angiotensin blockers

“…Several renin inhibitors have been identified since the 1980s, including enalkiren [79], CGP 38560 [80], remikiren [81], zankiren [82], ciprokiren [83], terlakiren [84], FK906 [85] and A-74273 [86]. Their efficacy in inhibiting renin and lowering blood pressure was demonstrated in animal experiments, although species specificity has somewhat limited in vivo animal studies.…”

Visible-Light-Induced Tertiary C(sp3)–H Sulfonylation: An Approach to Tertiary Sulfones

“…Sulfone functionalities are routinely considered in medicinal chemistry areas searching for antimalarial, anticancer, anti-inflammatory, anti-HIV, and antimicrobial activities. , Specifically, scaffolds containing tertiary sulfone funtionalities have found colossal importance in pharmaceuticals on account of their tremendous effects on the rate of drug metabolism. A wide range of tertiary sulfones used as clinically applied drugs or inhibitors are represented in Figure . − …”