Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor

Daniel W. Kung; Steven B. Coffey; Ryan M. Jones; Shawn Cabral; Wenhua Jiao; Michael Fichtner; Philip A. Carpino; Colin R. Rose; Richard F. Hank; Michael G. Lopaze; Roger Swartz; Hou Tommy Chen; Zachary Hendsch; Bruce Posner; Christopher F. Wielis; Brian Manning; Jeffrey Dubins; Ingrid A. Stock; Sam Varma; Mary Campbell; Demetria Debartola; Rachel Kosa-Maines; Stefanus J. Steyn; Kim F. McClure

doi:10.1016/j.bmcl.2012.05.024

Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor

Daniel W. Kung, Steven B. Coffey, Ryan M. Jones, Shawn Cabral, Wenhua Jiao, Michael Fichtner, Philip A. Carpino, Colin R. Rose, Richard F. Hank, Michael G. Lopaze, Roger Swartz, Hou Tommy Chen, Zachary Hendsch, Bruce Posner, Christopher F. Wielis, Brian Manning, Jeffrey Dubins, Ingrid A. Stock, Sam Varma, Mary CampbellDemetria Debartola, Rachel Kosa-Maines, Stefanus J. Steyn, Kim F. McClure

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

24 Scopus citations

Abstract

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in log P and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

Original language	English (US)
Pages (from-to)	4281-4287
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2012.05.024
State	Published - Jul 1 2012

Keywords

Antagonist
GHS-R1a
Ghrelin
Inverse agonist
Piperidine-azetidine
Spirocyclic

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2012.05.024

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Kung, D. W., Coffey, S. B., Jones, R. M., Cabral, S., Jiao, W., Fichtner, M., Carpino, P. A., Rose, C. R., Hank, R. F., Lopaze, M. G., Swartz, R., Chen, H. T., Hendsch, Z., Posner, B., Wielis, C. F., Manning, B., Dubins, J., Stock, I. A., Varma, S., ... McClure, K. F. (2012). Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor. Bioorganic and Medicinal Chemistry Letters, 22(13), 4281-4287. https://doi.org/10.1016/j.bmcl.2012.05.024

Kung, DW, Coffey, SB, Jones, RM, Cabral, S, Jiao, W, Fichtner, M, Carpino, PA, Rose, CR, Hank, RF, Lopaze, MG, Swartz, R, Chen, HT, Hendsch, Z, Posner, B, Wielis, CF, Manning, B, Dubins, J, Stock, IA, Varma, S, Campbell, M, Debartola, D, Kosa-Maines, R, Steyn, SJ & McClure, KF 2012, 'Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 13, pp. 4281-4287. https://doi.org/10.1016/j.bmcl.2012.05.024

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abstract = "The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in log P and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.",

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author = "Kung, {Daniel W.} and Coffey, {Steven B.} and Jones, {Ryan M.} and Shawn Cabral and Wenhua Jiao and Michael Fichtner and Carpino, {Philip A.} and Rose, {Colin R.} and Hank, {Richard F.} and Lopaze, {Michael G.} and Roger Swartz and Chen, {Hou Tommy} and Zachary Hendsch and Bruce Posner and Wielis, {Christopher F.} and Brian Manning and Jeffrey Dubins and Stock, {Ingrid A.} and Sam Varma and Mary Campbell and Demetria Debartola and Rachel Kosa-Maines and Steyn, {Stefanus J.} and McClure, {Kim F.}",

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AU - Coffey, Steven B.

AU - Jones, Ryan M.

AU - Cabral, Shawn

AU - Jiao, Wenhua

AU - Fichtner, Michael

AU - Carpino, Philip A.

AU - Rose, Colin R.

AU - Hank, Richard F.

AU - Lopaze, Michael G.

AU - Swartz, Roger

AU - Chen, Hou Tommy

AU - Hendsch, Zachary

AU - Posner, Bruce

AU - Wielis, Christopher F.

AU - Manning, Brian

AU - Dubins, Jeffrey

AU - Stock, Ingrid A.

AU - Varma, Sam

AU - Campbell, Mary

AU - Debartola, Demetria

AU - Kosa-Maines, Rachel

AU - Steyn, Stefanus J.

AU - McClure, Kim F.

PY - 2012/7/1

Y1 - 2012/7/1

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AB - The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in log P and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

KW - Antagonist

KW - GHS-R1a

KW - Ghrelin

KW - Inverse agonist

KW - Piperidine-azetidine

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Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor

Abstract

Keywords

ASJC Scopus subject areas

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