1. Academic Validation
  2. New, potent, selective, and short-acting peptidic V1a receptor agonists

New, potent, selective, and short-acting peptidic V1a receptor agonists

  • J Med Chem. 2011 Jul 14;54(13):4388-98. doi: 10.1021/jm200278m.
Kazimierz Wisniewski 1 Robert Galyean Hiroe Tariga Sudarkodi Alagarsamy Glenn Croston Joshua Heitzmann Arash Kohan Halina Wisniewska Régent Laporte Pierre J-M Rivière Claudio D Schteingart
Affiliations

Affiliation

  • 1 Ferring Research Institute Inc., San Diego, California 92121, United States. Kazimierz.Wisniewski@ferring.com
Abstract

[Arg(8)]vasopressin (AVP) produces vasoconstriction via V(1a) receptor (V(1a)R)-mediated vascular smooth muscle cell contraction and is being used to increase blood pressure in septic shock, a form of vasodilatory hypotension. However, AVP also induces V(2) receptor (V(2)R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V(1a)R agonist terlipressin (H-Gly(3)[Lys(8)]VP) also lacks selectivity vs the V(2)R and has sizably longer duration of action than AVP, preventing rapid titration of its vasopressor effect in the clinic. We designed and synthesized new short acting V(1a)R selective analogues of general structure [Xaa(2),Ile(3),Yaa(4),Zaa(8)]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe(2),Ile(3),Asn(Me(2))(4),Orn(8)]VP (31), [Phe(2),Ile(3),Asn((CH(2))(3)OH)(4),Orn(8)]VP (34), [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]VP (45), [Phe(2),Ile(3),Asn(Et)(4),Dab(8)]VP (49), [Thi(2),Ile(3),Orn(iPr)(8)]VP (59), [Cha(2),Ile(3),Asn(4),Orn(iPr)(8)]VP (68)) were tested by intravenous bolus in rats for duration of vasopressive action. Analogues 31, 34, 45, and 49 were as short-acting as AVP. Compound 45, FE 202158, is currently undergoing clinical trials in septic shock.

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