Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists

Daniel E. Jeffries; Jonathan O. Witt; Andrea L. McCollum; Kayla J. Temple; Miguel A. Hurtado; Joel M. Harp; Anna L. Blobaum; Craig W. Lindsley; Corey R. Hopkins

doi:10.1016/j.bmcl.2016.10.049

Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists

Daniel E. Jeffries, Jonathan O. Witt, Andrea L. McCollum, Kayla J. Temple, Miguel A. Hurtado, Joel M. Harp, Anna L. Blobaum, Craig W. Lindsley, Corey R. Hopkins

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

11 Scopus citations

Abstract

Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D₄) antagonists. A series of compounds from this scaffold are highly potent against the D₄receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.

Original language	English (US)
Pages (from-to)	5757-5764
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2016.10.049
State	Published - 2016

Keywords

Addiction
Difluoropiperidine
Dopamine 4 receptor
PD-LIDs
Selectivity

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2016.10.049

Cite this

Jeffries, D. E., Witt, J. O., McCollum, A. L., Temple, K. J., Hurtado, M. A., Harp, J. M., Blobaum, A. L., Lindsley, C. W., & Hopkins, C. R. (2016). Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists. Bioorganic and Medicinal Chemistry Letters, 26(23), 5757-5764. https://doi.org/10.1016/j.bmcl.2016.10.049

Jeffries, DE, Witt, JO, McCollum, AL, Temple, KJ, Hurtado, MA, Harp, JM, Blobaum, AL, Lindsley, CW & Hopkins, CR 2016, 'Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 23, pp. 5757-5764. https://doi.org/10.1016/j.bmcl.2016.10.049

@article{26eeea682b4e4001aa020ab670b6889d,

title = "Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists",

abstract = "Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.",

keywords = "Addiction, Difluoropiperidine, Dopamine 4 receptor, PD-LIDs, Selectivity",

author = "Jeffries, {Daniel E.} and Witt, {Jonathan O.} and McCollum, {Andrea L.} and Temple, {Kayla J.} and Hurtado, {Miguel A.} and Harp, {Joel M.} and Blobaum, {Anna L.} and Lindsley, {Craig W.} and Hopkins, {Corey R.}",

note = "Funding Information: The authors would like to thank the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research for research support for CRH (MJFF Grant ID: 10000) and Jarrett Foster, Sichen Chang, and Xiaoyan Zhan for their contributions to the DMPK screening tier. Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

year = "2016",

doi = "10.1016/j.bmcl.2016.10.049",

language = "English (US)",

volume = "26",

pages = "5757--5764",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "23",

}

TY - JOUR

T1 - Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists

AU - Jeffries, Daniel E.

AU - Witt, Jonathan O.

AU - McCollum, Andrea L.

AU - Temple, Kayla J.

AU - Hurtado, Miguel A.

AU - Harp, Joel M.

AU - Blobaum, Anna L.

AU - Lindsley, Craig W.

AU - Hopkins, Corey R.

N1 - Funding Information: The authors would like to thank the Michael J. Fox Foundation for Parkinson’s Research for research support for CRH (MJFF Grant ID: 10000) and Jarrett Foster, Sichen Chang, and Xiaoyan Zhan for their contributions to the DMPK screening tier. Publisher Copyright: © 2016 Elsevier Ltd

PY - 2016

Y1 - 2016

N2 - Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.

AB - Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.

KW - Addiction

KW - Difluoropiperidine

KW - Dopamine 4 receptor

KW - PD-LIDs

KW - Selectivity

UR - http://www.scopus.com/inward/record.url?scp=84996566012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84996566012&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.10.049

DO - 10.1016/j.bmcl.2016.10.049

M3 - Article

C2 - 28327307

AN - SCOPUS:84996566012

SN - 0960-894X

VL - 26

SP - 5757

EP - 5764

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -