The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine

Peter Lin; Lehua Chang; Robert J. DeVita; Jonathan R. Young; Ronsar Eid; Xinchun Tong; Song Zheng; Richard G. Ball; Nancy N. Tsou; Gary G. Chicchi; Marc M. Kurtz; Kwei Lan C. Tsao; Alan Wheeldon; Emma J. Carlson; Wai Si Eng; H. Donald Burns; Richard J. Hargreaves; Sander G. Mills

doi:10.1016/j.bmcl.2007.06.085

The discovery of potent, selective, and orally bioavailable hNK₁ antagonists derived from pyrrolidine

Peter Lin, Lehua Chang, Robert J. DeVita, Jonathan R. Young, Ronsar Eid, Xinchun Tong, Song Zheng, Richard G. Ball, Nancy N. Tsou, Gary G. Chicchi, Marc M. Kurtz, Kwei Lan C. Tsao, Alan Wheeldon, Emma J. Carlson, Wai Si Eng, H. Donald Burns, Richard J. Hargreaves, Sander G. Mills

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

13 Scopus citations

Abstract

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK₁ antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ₉₀ ∼ 300 ng/ml.

Original language	English
Pages (from-to)	5191-5198
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2007.06.085
State	Published - 15 Sep 2007
Externally published	Yes

Keywords

NK
Neurokinin NK antagonist
Substance P antagonist
Tachykinin NK antagonist

Access to Document

10.1016/j.bmcl.2007.06.085

Cite this

Lin, P., Chang, L., DeVita, R. J., Young, J. R., Eid, R., Tong, X., Zheng, S., Ball, R. G., Tsou, N. N., Chicchi, G. G., Kurtz, M. M., Tsao, K. L. C., Wheeldon, A., Carlson, E. J., Eng, W. S., Burns, H. D., Hargreaves, R. J., & Mills, S. G. (2007). The discovery of potent, selective, and orally bioavailable hNK₁ antagonists derived from pyrrolidine. Bioorganic and Medicinal Chemistry Letters, 17(18), 5191-5198. https://doi.org/10.1016/j.bmcl.2007.06.085

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title = "The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine",

abstract = "SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK1 antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ90 ∼ 300 ng/ml.",

keywords = "NK, Neurokinin NK antagonist, Substance P antagonist, Tachykinin NK antagonist",

author = "Peter Lin and Lehua Chang and DeVita, {Robert J.} and Young, {Jonathan R.} and Ronsar Eid and Xinchun Tong and Song Zheng and Ball, {Richard G.} and Tsou, {Nancy N.} and Chicchi, {Gary G.} and Kurtz, {Marc M.} and Tsao, {Kwei Lan C.} and Alan Wheeldon and Carlson, {Emma J.} and Eng, {Wai Si} and Burns, {H. Donald} and Hargreaves, {Richard J.} and Mills, {Sander G.}",

year = "2007",

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doi = "10.1016/j.bmcl.2007.06.085",

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Lin, P, Chang, L, DeVita, RJ, Young, JR, Eid, R, Tong, X, Zheng, S, Ball, RG, Tsou, NN, Chicchi, GG, Kurtz, MM, Tsao, KLC, Wheeldon, A, Carlson, EJ, Eng, WS, Burns, HD, Hargreaves, RJ & Mills, SG 2007, 'The discovery of potent, selective, and orally bioavailable hNK₁ antagonists derived from pyrrolidine', Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 18, pp. 5191-5198. https://doi.org/10.1016/j.bmcl.2007.06.085

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AU - Lin, Peter

AU - Chang, Lehua

AU - DeVita, Robert J.

AU - Young, Jonathan R.

AU - Eid, Ronsar

AU - Tong, Xinchun

AU - Zheng, Song

AU - Ball, Richard G.

AU - Tsou, Nancy N.

AU - Chicchi, Gary G.

AU - Kurtz, Marc M.

AU - Tsao, Kwei Lan C.

AU - Wheeldon, Alan

AU - Carlson, Emma J.

AU - Eng, Wai Si

AU - Burns, H. Donald

AU - Hargreaves, Richard J.

AU - Mills, Sander G.

PY - 2007/9/15

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KW - Neurokinin NK antagonist

KW - Substance P antagonist

KW - Tachykinin NK antagonist

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