Pharmacological Characterization of FE 202158, a Novel, Potent, Selective, and Short-Acting Peptidic Vasopressin V_1aReceptor Full Agonist for the Treatment of Vasodilatory Hypotension

Abstract

R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V 2 R (selectivity ratio of 1:18:0.2:92; human V 1a R EC 50 ϭ 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC 50 ϭ 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED 50 ϭ 4.0 versus 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V 2 R-mediated antidiuretic activity in rats by intravenous infusion at its ED 50 for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V 1a R activity is desirable but V 2 R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its shortacting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety.

The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

“…In the present study, we tested the novel selective and short-acting V 1a R agonist selepressin (FE 202158) (32, 33) versus AVP as a titrated first-line vasopressor therapy in an established conscious ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis (34, 35) 1 .…”

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

“…158 The treatment of vasodilatory hypotension as observed in septic shock would however require a V 1a R-selective agonist with a short half-life. 159 The synthesis of analogs of AVP modified in positions 2, 3, 4, and 8 afforded a series of compounds with a suitable profile, among them 80 (FE202158, Figure 8.29), 158 which was found to be a potent and selective full agonist at the human V 1a receptor (Table 8.5) and also a potent vasoconstrictor in vivo in rats, as shown by dose-dependent reduction of ear skin blood flow (ED 50 of 4.0 pmol kg À1 min À1 ; given by constant intravenous infusion), with no V 2 R mediated antidiuretic activity. 159 Macrocycle 80 (FE202158) was chosen for clinical trials for the treatment of septic shock.…”

A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design

“…The duration of action of terlipressin is longer than that of vasopressin and is due to the stepwise cleavage of the N-terminal glycyl residues of terlipressin by various tissue peptidases, resulting in release of the pharmacologically active metabolite lysine-vasopressin, which has >95% of the activity of the drug. 35 It is for this reason terlipressin may be considered a prodrug. Once formed, lysine-vasopressin is eliminated by plasma peptidase losing its vasopressinergic activity.…”