Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V1b receptor antagonists

Susan E. Napier; Jeffrey J. Letourneau; Nasrin Ansari; Douglas S. Auld; James Baker; Stuart Best; Leigh Campbell-Wan; Jui Hsiang Chan; Mark Craighead; Hema Desai; Katharine A. Goan; Koc Kan Ho; Ellen G.J. Hulskotte; Cliona P. MacSweeney; Rachel Milne; J. Richard Morphy; Irina Neagu; Michael H.J. Ohlmeyer; Ard W.M.M. Peeters; Jeremy Presland; Chris Riviello; Ge S.F. Ruigt; Fiona J. Thomson; Heather A. Zanetakos; Jiuqiao Zhao; Maria L. Webb

doi:10.1016/j.bmcl.2010.12.081

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V_1b receptor antagonists

Susan E. Napier, Jeffrey J. Letourneau, Nasrin Ansari, Douglas S. Auld, James Baker, Stuart Best, Leigh Campbell-Wan, Jui Hsiang Chan, Mark Craighead, Hema Desai, Katharine A. Goan, Koc Kan Ho, Ellen G.J. Hulskotte, Cliona P. MacSweeney, Rachel Milne, J. Richard Morphy, Irina Neagu, Michael H.J. Ohlmeyer, Ard W.M.M. Peeters, Jeremy PreslandChris Riviello, Ge S.F. Ruigt, Fiona J. Thomson, Heather A. Zanetakos, Jiuqiao Zhao, Maria L. Webb

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V_1b (V₃) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V_1b receptor and good selectivity with respect to related receptors V_1a, V₂ and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

Original language	English
Pages (from-to)	1871-1875
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2010.12.081
State	Published - 15 Mar 2011
Externally published	Yes

Keywords

HPA axis
Vasopressin

Access to Document

10.1016/j.bmcl.2010.12.081

Cite this

Napier, S. E., Letourneau, J. J., Ansari, N., Auld, D. S., Baker, J., Best, S., Campbell-Wan, L., Chan, J. H., Craighead, M., Desai, H., Goan, K. A., Ho, K. K., Hulskotte, E. G. J., MacSweeney, C. P., Milne, R., Morphy, J. R., Neagu, I., Ohlmeyer, M. H. J., Peeters, A. W. M. M., ... Webb, M. L. (2011). Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V_1b receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 21(6), 1871-1875. https://doi.org/10.1016/j.bmcl.2010.12.081

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title = "Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V1b receptor antagonists",

abstract = "Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.",

keywords = "HPA axis, Vasopressin",

author = "Napier, {Susan E.} and Letourneau, {Jeffrey J.} and Nasrin Ansari and Auld, {Douglas S.} and James Baker and Stuart Best and Leigh Campbell-Wan and Chan, {Jui Hsiang} and Mark Craighead and Hema Desai and Goan, {Katharine A.} and Ho, {Koc Kan} and Hulskotte, {Ellen G.J.} and MacSweeney, {Cliona P.} and Rachel Milne and Morphy, {J. Richard} and Irina Neagu and Ohlmeyer, {Michael H.J.} and Peeters, {Ard W.M.M.} and Jeremy Presland and Chris Riviello and Ruigt, {Ge S.F.} and Thomson, {Fiona J.} and Zanetakos, {Heather A.} and Jiuqiao Zhao and Webb, {Maria L.}",

year = "2011",

month = mar,

day = "15",

doi = "10.1016/j.bmcl.2010.12.081",

language = "English",

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pages = "1871--1875",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Napier, SE, Letourneau, JJ, Ansari, N, Auld, DS, Baker, J, Best, S, Campbell-Wan, L, Chan, JH, Craighead, M, Desai, H, Goan, KA, Ho, KK, Hulskotte, EGJ, MacSweeney, CP, Milne, R, Morphy, JR, Neagu, I, Ohlmeyer, MHJ, Peeters, AWMM, Presland, J, Riviello, C, Ruigt, GSF, Thomson, FJ, Zanetakos, HA, Zhao, J & Webb, ML 2011, 'Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V_1b receptor antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 6, pp. 1871-1875. https://doi.org/10.1016/j.bmcl.2010.12.081

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T1 - Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl) acetamide vasopressin V1b receptor antagonists

AU - Napier, Susan E.

AU - Letourneau, Jeffrey J.

AU - Ansari, Nasrin

AU - Auld, Douglas S.

AU - Baker, James

AU - Best, Stuart

AU - Campbell-Wan, Leigh

AU - Chan, Jui Hsiang

AU - Craighead, Mark

AU - Desai, Hema

AU - Goan, Katharine A.

AU - Ho, Koc Kan

AU - Hulskotte, Ellen G.J.

AU - MacSweeney, Cliona P.

AU - Milne, Rachel

AU - Morphy, J. Richard

AU - Neagu, Irina

AU - Ohlmeyer, Michael H.J.

AU - Peeters, Ard W.M.M.

AU - Presland, Jeremy

AU - Riviello, Chris

AU - Ruigt, Ge S.F.

AU - Thomson, Fiona J.

AU - Zanetakos, Heather A.

AU - Zhao, Jiuqiao

AU - Webb, Maria L.

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

AB - Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

KW - HPA axis

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