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New, Potent, Selective, and Short-Acting Peptidic V1a Receptor Agonists

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Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States
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Cite this: J. Med. Chem. 2011, 54, 13, 4388–4398
Publication Date (Web):June 20, 2011
https://doi.org/10.1021/jm200278m
Copyright © 2011 American Chemical Society
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    [Arg8]vasopressin (AVP) produces vasoconstriction via V1a receptor (V1aR)-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 V2 receptor (V2R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V1aR agonist terlipressin (H-Gly3[Lys8]VP) also lacks selectivity vs the V2R 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 V1aR selective analogues of general structure [Xaa2,Ile3,Yaa4,Zaa8]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe2,Ile3,Asn(Me2)4,Orn8]VP (31), [Phe2,Ile3,Asn((CH2)3OH)4,Orn8]VP (34), [Phe2,Ile3,Hgn4,Orn(iPr)8]VP (45), [Phe2,Ile3,Asn(Et)4,Dab8]VP (49), [Thi2,Ile3,Orn(iPr)8]VP (59), [Cha2,Ile3,Asn4,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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    Detailed synthetic procedures and physicochemical properties of compounds 1–7 and 8–70. This material is available free of charge via the Internet at http://pubs.acs.org.

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