Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity

Changyou Zhou; Margareta Garcia-Calvo; Shirly Pinto; Matthew Lombardo; Zhe Feng; Kate Bender; Kellyann D. Pryor; Urmi R. Bhatt; Renee M. Chabin; Wayne M. Geissler; Zhu Shen; Xinchun Tong; Zhoupeng Zhang; Kenny K. Wong; Ranabir Sinha Roy; Kevin T. Chapman; Lihu Yang; Yusheng Xiong

doi:10.1021/jm101013m

Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity

Changyou Zhou
, Margareta Garcia-Calvo
, Shirly Pinto
, Matthew Lombardo
, Zhe Feng
, Kate Bender
, Kellyann D. Pryor
, Urmi R. Bhatt
, Renee M. Chabin
, Wayne M. Geissler
, Zhu Shen
, Xinchun Tong
, Zhoupeng Zhang
, Kenny K. Wong
, Ranabir Sinha Roy
, Kevin T. Chapman
, Lihu Yang
, Yusheng Xiong

Department of Chemistry and Chemical Biology

Merck

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

54 Scopus citations

Abstract

Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC ₅₀ values of 1 and 2 nM and is not active (IC₅₀ > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP^-/- and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.

Original language	English
Pages (from-to)	7251-7263
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	19
DOIs	https://doi.org/10.1021/jm101013m
State	Published - 14 Oct 2010

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Zhou, C., Garcia-Calvo, M., Pinto, S., Lombardo, M., Feng, Z., Bender, K., Pryor, K. D., Bhatt, U. R., Chabin, R. M., Geissler, W. M., Shen, Z., Tong, X., Zhang, Z., Wong, K. K., Roy, R. S., Chapman, K. T., Yang, L., & Xiong, Y. (2010). Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity. Journal of Medicinal Chemistry, 53(19), 7251-7263. https://doi.org/10.1021/jm101013m

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title = "Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity",

abstract = "Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC 50 values of 1 and 2 nM and is not active (IC50 > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP-/- and WT mice at 100 mg/kg for 5 days resulted in a 5\% reduction in body weight in WT mice and a 1\% reduction in PrCP KO mice.",

author = "Changyou Zhou and Margareta Garcia-Calvo and Shirly Pinto and Matthew Lombardo and Zhe Feng and Kate Bender and Pryor, \{Kellyann D.\} and Bhatt, \{Urmi R.\} and Chabin, \{Renee M.\} and Geissler, \{Wayne M.\} and Zhu Shen and Xinchun Tong and Zhoupeng Zhang and Wong, \{Kenny K.\} and Roy, \{Ranabir Sinha\} and Chapman, \{Kevin T.\} and Lihu Yang and Yusheng Xiong",

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doi = "10.1021/jm101013m",

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Zhou, C, Garcia-Calvo, M, Pinto, S, Lombardo, M, Feng, Z, Bender, K, Pryor, KD, Bhatt, UR, Chabin, RM, Geissler, WM, Shen, Z, Tong, X, Zhang, Z, Wong, KK, Roy, RS, Chapman, KT, Yang, L & Xiong, Y 2010, 'Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity', Journal of Medicinal Chemistry, vol. 53, no. 19, pp. 7251-7263. https://doi.org/10.1021/jm101013m

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T1 - Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity

AU - Zhou, Changyou

AU - Garcia-Calvo, Margareta

AU - Pinto, Shirly

AU - Lombardo, Matthew

AU - Feng, Zhe

AU - Bender, Kate

AU - Pryor, Kellyann D.

AU - Bhatt, Urmi R.

AU - Chabin, Renee M.

AU - Geissler, Wayne M.

AU - Shen, Zhu

AU - Tong, Xinchun

AU - Zhang, Zhoupeng

AU - Wong, Kenny K.

AU - Roy, Ranabir Sinha

AU - Chapman, Kevin T.

AU - Yang, Lihu

AU - Xiong, Yusheng

PY - 2010/10/14

Y1 - 2010/10/14

N2 - Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC 50 values of 1 and 2 nM and is not active (IC50 > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP-/- and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.

AB - Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC 50 values of 1 and 2 nM and is not active (IC50 > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP-/- and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.

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JO - Journal of Medicinal Chemistry

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IS - 19

ER -

Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity

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