Pharmacological Characterization of FE 202158, a Novel, Potent, Selective, and Short-Acting Peptidic Vasopressin V 1a Receptor 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

Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders

ABSTRACTProlactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females

New, Potent, and Selective Peptidic Oxytocin Receptor Agonists

Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V₂ receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing <i>N</i>-alkylglycines in position 7 with excellent selectivity versus the related V_1a, V_1b, and V₂ vasopressin receptors and short half-life: agonists <b>31</b> ([2-ThiMeGly⁷]­dOT), <b>47</b> (carba-6-[Phe²,BuGly⁷]­dOT), <b>55</b> (carba-6-[3-MeBzlGly⁷]­dOT), and <b>57</b> (carba-1-[4-FBzlGly⁷]­dOT) have EC₅₀ values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC₅₀ at hV_1aR > 500 nM, and total clearance in rats in the range of 60–80 mL min^–1 kg^–1. Compound <b>57</b> (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support

Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide‑2 (GLP-2) Analogues with Low Systemic Clearance

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. <i>In vitro</i> receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues <b>69</b> ([Gly²,Nle¹⁰,d-Thi¹¹,Phe¹⁶]­hGLP-2-(1−30)-NH₂), <b>72</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-OH), <b>73</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NH₂), <b>81</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NHEt), and <b>85</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NH-((CH₂)₂O)₄-(CH₂)₂-CONH₂) displayed the desired profiles (EC₅₀ (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound <b>73</b> (FE 203799) was selected as a candidate for clinical development