Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()

Petr Vachal; Joseph L. Duffy; Louis Charles Campeau; Rupesh P. Amin; Kaushik Mitra; Beth Ann Murphy; Pengcheng P. Shao; Peter J. Sinclair; Feng Ye; Revathi Katipally; Zhijian Lu; Debra Ondeyka; Yi Heng Chen; Kake Zhao; Wanying Sun; Sriram Tyagarajan; Jianming Bao; Sheng Ping Wang; Josee Cote; Concetta Lipardi; Daniel Metzger; Dennis Leung; Georgy Hartmann; Gordon K. Wollenberg; Jian Liu; Lushi Tan; Yingju Xu; Qinghao Chen; Guiquan Liu; Robert O. Blaustein; Douglas G. Johns

doi:10.1021/acs.jmedchem.1c00959

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()

Petr Vachal, Joseph L. Duffy, Louis Charles Campeau, Rupesh P. Amin, Kaushik Mitra, Beth Ann Murphy, Pengcheng P. Shao, Peter J. Sinclair, Feng Ye, Revathi Katipally, Zhijian Lu, Debra Ondeyka, Yi Heng Chen, Kake Zhao, Wanying Sun, Sriram Tyagarajan, Jianming Bao, Sheng Ping Wang, Josee Cote, Concetta LipardiDaniel Metzger, Dennis Leung, Georgy Hartmann, Gordon K. Wollenberg, Jian Liu, Lushi Tan, Yingju Xu, Qinghao Chen, Guiquan Liu, Robert O. Blaustein, Douglas G. Johns

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

11 Scopus citations

Abstract

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Original language	English (US)
Pages (from-to)	13215-13258
Number of pages	44
Journal	Journal of medicinal chemistry
Volume	64
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00959
State	Published - Sep 23 2021
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c00959

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Vachal, P., Duffy, J. L., Campeau, L. C., Amin, R. P., Mitra, K., Murphy, B. A., Shao, P. P., Sinclair, P. J., Ye, F., Katipally, R., Lu, Z., Ondeyka, D., Chen, Y. H., Zhao, K., Sun, W., Tyagarajan, S., Bao, J., Wang, S. P., Cote, J., ... Johns, D. G. (2021). Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties (). Journal of medicinal chemistry, 64(18), 13215-13258. https://doi.org/10.1021/acs.jmedchem.1c00959

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title = "Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()",

abstract = "Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.",

author = "Petr Vachal and Duffy, {Joseph L.} and Campeau, {Louis Charles} and Amin, {Rupesh P.} and Kaushik Mitra and Murphy, {Beth Ann} and Shao, {Pengcheng P.} and Sinclair, {Peter J.} and Feng Ye and Revathi Katipally and Zhijian Lu and Debra Ondeyka and Chen, {Yi Heng} and Kake Zhao and Wanying Sun and Sriram Tyagarajan and Jianming Bao and Wang, {Sheng Ping} and Josee Cote and Concetta Lipardi and Daniel Metzger and Dennis Leung and Georgy Hartmann and Wollenberg, {Gordon K.} and Jian Liu and Lushi Tan and Yingju Xu and Qinghao Chen and Guiquan Liu and Blaustein, {Robert O.} and Johns, {Douglas G.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Chemical Society",

year = "2021",

month = sep,

day = "23",

doi = "10.1021/acs.jmedchem.1c00959",

language = "English (US)",

volume = "64",

pages = "13215--13258",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "18",

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Vachal, P, Duffy, JL, Campeau, LC, Amin, RP, Mitra, K, Murphy, BA, Shao, PP, Sinclair, PJ, Ye, F, Katipally, R, Lu, Z, Ondeyka, D, Chen, YH, Zhao, K, Sun, W, Tyagarajan, S, Bao, J, Wang, SP, Cote, J, Lipardi, C, Metzger, D, Leung, D, Hartmann, G, Wollenberg, GK, Liu, J, Tan, L, Xu, Y, Chen, Q, Liu, G, Blaustein, RO & Johns, DG 2021, 'Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()', Journal of medicinal chemistry, vol. 64, no. 18, pp. 13215-13258. https://doi.org/10.1021/acs.jmedchem.1c00959

TY - JOUR

T1 - Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()

AU - Vachal, Petr

AU - Duffy, Joseph L.

AU - Campeau, Louis Charles

AU - Amin, Rupesh P.

AU - Mitra, Kaushik

AU - Murphy, Beth Ann

AU - Shao, Pengcheng P.

AU - Sinclair, Peter J.

AU - Ye, Feng

AU - Katipally, Revathi

AU - Lu, Zhijian

AU - Ondeyka, Debra

AU - Chen, Yi Heng

AU - Zhao, Kake

AU - Sun, Wanying

AU - Tyagarajan, Sriram

AU - Bao, Jianming

AU - Wang, Sheng Ping

AU - Cote, Josee

AU - Lipardi, Concetta

AU - Metzger, Daniel

AU - Leung, Dennis

AU - Hartmann, Georgy

AU - Wollenberg, Gordon K.

AU - Liu, Jian

AU - Tan, Lushi

AU - Xu, Yingju

AU - Chen, Qinghao

AU - Liu, Guiquan

AU - Blaustein, Robert O.

AU - Johns, Douglas G.

PY - 2021/9/23

Y1 - 2021/9/23

N2 - Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

AB - Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

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U2 - 10.1021/acs.jmedchem.1c00959

DO - 10.1021/acs.jmedchem.1c00959

M3 - Article

C2 - 34375108

AN - SCOPUS:85113854941

SN - 0022-2623

VL - 64

SP - 13215

EP - 13258

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 18

ER -

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()

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