Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

Jinlong Jiang; Jaime L. Bunda; Geoge A. Doss; Gary G. Chicchi; Marc M. Kurtz; Kwei Lan C. Tsao; Xinchun Tong; Song Zheng; Alana Upthagrove; Koppara Samuel; Richard Tschirret-Guth; Sanjeev Kumar; Alan Wheeldon; Emma J. Carlson; Richard Hargreaves; Donald Burns; Terence Hamill; Christine Ryan; Stephen M. Krause; Wai Si Eng; Robert J. DeVita; Sander G. Mills

doi:10.1021/jm8016514

Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

Jinlong Jiang, Jaime L. Bunda, Geoge A. Doss, Gary G. Chicchi, Marc M. Kurtz, Kwei Lan C. Tsao, Xinchun Tong, Song Zheng, Alana Upthagrove, Koppara Samuel, Richard Tschirret-Guth, Sanjeev Kumar, Alan Wheeldon, Emma J. Carlson, Richard Hargreaves, Donald Burns, Terence Hamill, Christine Ryan, Stephen M. Krause, Wai Si EngRobert J. DeVita, Sander G. Mills

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

21 Scopus citations

Abstract

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy} -4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK1 receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK1 antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

Original language	English
Pages (from-to)	3039-3046
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	9
DOIs	https://doi.org/10.1021/jm8016514
State	Published - 14 May 2009
Externally published	Yes

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Jiang, J., Bunda, J. L., Doss, G. A., Chicchi, G. G., Kurtz, M. M., Tsao, K. L. C., Tong, X., Zheng, S., Upthagrove, A., Samuel, K., Tschirret-Guth, R., Kumar, S., Wheeldon, A., Carlson, E. J., Hargreaves, R., Burns, D., Hamill, T., Ryan, C., Krause, S. M., ... Mills, S. G. (2009). Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. Journal of Medicinal Chemistry, 52(9), 3039-3046. https://doi.org/10.1021/jm8016514

@article{2781b45903ea4e6eb474085fce32098c,

title = "Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists",

abstract = "3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy} -4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK1 receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK1 antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.",

author = "Jinlong Jiang and Bunda, {Jaime L.} and Doss, {Geoge A.} and Chicchi, {Gary G.} and Kurtz, {Marc M.} and Tsao, {Kwei Lan C.} and Xinchun Tong and Song Zheng and Alana Upthagrove and Koppara Samuel and Richard Tschirret-Guth and Sanjeev Kumar and Alan Wheeldon and Carlson, {Emma J.} and Richard Hargreaves and Donald Burns and Terence Hamill and Christine Ryan and Krause, {Stephen M.} and Eng, {Wai Si} and DeVita, {Robert J.} and Mills, {Sander G.}",

year = "2009",

month = may,

day = "14",

doi = "10.1021/jm8016514",

language = "English",

volume = "52",

pages = "3039--3046",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "9",

}

Jiang, J, Bunda, JL, Doss, GA, Chicchi, GG, Kurtz, MM, Tsao, KLC, Tong, X, Zheng, S, Upthagrove, A, Samuel, K, Tschirret-Guth, R, Kumar, S, Wheeldon, A, Carlson, EJ, Hargreaves, R, Burns, D, Hamill, T, Ryan, C, Krause, SM, Eng, WS, DeVita, RJ & Mills, SG 2009, 'Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists', Journal of Medicinal Chemistry, vol. 52, no. 9, pp. 3039-3046. https://doi.org/10.1021/jm8016514

TY - JOUR

T1 - Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

AU - Jiang, Jinlong

AU - Bunda, Jaime L.

AU - Doss, Geoge A.

AU - Chicchi, Gary G.

AU - Kurtz, Marc M.

AU - Tsao, Kwei Lan C.

AU - Tong, Xinchun

AU - Zheng, Song

AU - Upthagrove, Alana

AU - Samuel, Koppara

AU - Tschirret-Guth, Richard

AU - Kumar, Sanjeev

AU - Wheeldon, Alan

AU - Carlson, Emma J.

AU - Hargreaves, Richard

AU - Burns, Donald

AU - Hamill, Terence

AU - Ryan, Christine

AU - Krause, Stephen M.

AU - Eng, Wai Si

AU - DeVita, Robert J.

AU - Mills, Sander G.

PY - 2009/5/14

Y1 - 2009/5/14

N2 - 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy} -4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK1 receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK1 antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

AB - 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy} -4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]-cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK1) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK1 receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK1 antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

UR - http://www.scopus.com/inward/record.url?scp=65649132794&partnerID=8YFLogxK

U2 - 10.1021/jm8016514

DO - 10.1021/jm8016514

M3 - Article

C2 - 19354254

AN - SCOPUS:65649132794

SN - 0022-2623

VL - 52

SP - 3039

EP - 3046

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

Abstract

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