Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

Shuwen He; Zhong Lai; Qingmei Hong; Jackie Shang; Mikhail Reibarkh; Jeffrey T. Kuethe; Jian Liu; Deodial Guiadeen; Arto D. Krikorian; Timothy A. Cernak; Kevin D. Dykstra; Donald M. Sperbeck; Zhicai Wu; Yang Yu; Ginger X. Yang; Tianying Jian; Andreas Verras; Lisa M. Sonatore; Judyann Wiltsie; Christine C. Chung; Beth A. Murphy; Judith N. Gorski; Jinqi Liu; Jianying Xiao; Michael Wolff; Sharon X. Tong; Maria Madeira; Bindhu V. Karanam; Dong Ming Shen; James M. Balkovec; Shirly Pinto; Ravi P. Nargund; Robert J. DeVita

doi:10.1016/j.bmcl.2019.03.025

Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

Shuwen He, Zhong Lai, Qingmei Hong, Jackie Shang, Mikhail Reibarkh, Jeffrey T. Kuethe, Jian Liu, Deodial Guiadeen, Arto D. Krikorian, Timothy A. Cernak, Kevin D. Dykstra, Donald M. Sperbeck, Zhicai Wu, Yang Yu, Ginger X. Yang, Tianying Jian, Andreas Verras, Lisa M. Sonatore, Judyann Wiltsie, Christine C. ChungBeth A. Murphy, Judith N. Gorski, Jinqi Liu, Jianying Xiao, Michael Wolff, Sharon X. Tong, Maria Madeira, Bindhu V. Karanam, Dong Ming Shen, James M. Balkovec, Shirly Pinto, Ravi P. Nargund, Robert J. DeVita

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

4 Scopus citations

Abstract

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

Original language	English
Pages (from-to)	1182-1186
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2019.03.025
State	Published - 15 May 2019
Externally published	Yes

Keywords

Benzimidazole
DGAT1
Inhibitor
Isomerization
[3.1.0] bicyclohexane carboxylic acid

Access to Document

10.1016/j.bmcl.2019.03.025

Cite this

He, S., Lai, Z., Hong, Q., Shang, J., Reibarkh, M., Kuethe, J. T., Liu, J., Guiadeen, D., Krikorian, A. D., Cernak, T. A., Dykstra, K. D., Sperbeck, D. M., Wu, Z., Yu, Y., Yang, G. X., Jian, T., Verras, A., Sonatore, L. M., Wiltsie, J., ... DeVita, R. J. (2019). Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Bioorganic and Medicinal Chemistry Letters, 29(10), 1182-1186. https://doi.org/10.1016/j.bmcl.2019.03.025

@article{6cd546d8668d4044a7f212754f6d2fac,

title = "Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety",

abstract = "Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.",

keywords = "Benzimidazole, DGAT1, Inhibitor, Isomerization, [3.1.0] bicyclohexane carboxylic acid",

author = "Shuwen He and Zhong Lai and Qingmei Hong and Jackie Shang and Mikhail Reibarkh and Kuethe, {Jeffrey T.} and Jian Liu and Deodial Guiadeen and Krikorian, {Arto D.} and Cernak, {Timothy A.} and Dykstra, {Kevin D.} and Sperbeck, {Donald M.} and Zhicai Wu and Yang Yu and Yang, {Ginger X.} and Tianying Jian and Andreas Verras and Sonatore, {Lisa M.} and Judyann Wiltsie and Chung, {Christine C.} and Murphy, {Beth A.} and Gorski, {Judith N.} and Jinqi Liu and Jianying Xiao and Michael Wolff and Tong, {Sharon X.} and Maria Madeira and Karanam, {Bindhu V.} and Shen, {Dong Ming} and Balkovec, {James M.} and Shirly Pinto and Nargund, {Ravi P.} and DeVita, {Robert J.}",

note = "Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2019.03.025",

language = "English",

volume = "29",

pages = "1182--1186",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

number = "10",

}

He, S, Lai, Z, Hong, Q, Shang, J, Reibarkh, M, Kuethe, JT, Liu, J, Guiadeen, D, Krikorian, AD, Cernak, TA, Dykstra, KD, Sperbeck, DM, Wu, Z, Yu, Y, Yang, GX, Jian, T, Verras, A, Sonatore, LM, Wiltsie, J, Chung, CC, Murphy, BA, Gorski, JN, Liu, J, Xiao, J, Wolff, M, Tong, SX, Madeira, M, Karanam, BV, Shen, DM, Balkovec, JM, Pinto, S, Nargund, RP & DeVita, RJ 2019, 'Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 10, pp. 1182-1186. https://doi.org/10.1016/j.bmcl.2019.03.025

TY - JOUR

T1 - Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

AU - He, Shuwen

AU - Lai, Zhong

AU - Hong, Qingmei

AU - Shang, Jackie

AU - Reibarkh, Mikhail

AU - Kuethe, Jeffrey T.

AU - Liu, Jian

AU - Guiadeen, Deodial

AU - Krikorian, Arto D.

AU - Cernak, Timothy A.

AU - Dykstra, Kevin D.

AU - Sperbeck, Donald M.

AU - Wu, Zhicai

AU - Yu, Yang

AU - Yang, Ginger X.

AU - Jian, Tianying

AU - Verras, Andreas

AU - Sonatore, Lisa M.

AU - Wiltsie, Judyann

AU - Chung, Christine C.

AU - Murphy, Beth A.

AU - Gorski, Judith N.

AU - Liu, Jinqi

AU - Xiao, Jianying

AU - Wolff, Michael

AU - Tong, Sharon X.

AU - Madeira, Maria

AU - Karanam, Bindhu V.

AU - Shen, Dong Ming

AU - Balkovec, James M.

AU - Pinto, Shirly

AU - Nargund, Ravi P.

AU - DeVita, Robert J.

PY - 2019/5/15

Y1 - 2019/5/15

N2 - Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

AB - Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

KW - Benzimidazole

KW - DGAT1

KW - Inhibitor

KW - Isomerization

KW - [3.1.0] bicyclohexane carboxylic acid

UR - http://www.scopus.com/inward/record.url?scp=85063347232&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2019.03.025

DO - 10.1016/j.bmcl.2019.03.025

M3 - Article

C2 - 30926247

AN - SCOPUS:85063347232

SN - 0960-894X

VL - 29

SP - 1182

EP - 1186

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 10

ER -

Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

Abstract

Keywords

Access to Document

Fingerprint

Cite this