Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor

James M. Apgar; Robert R. Wilkening; Dann L. Parker; Dongfang Meng; Kenneth J. Wildonger; Donald Sperbeck; Mark L. Greenlee; James M. Balkovec; Amy M. Flattery; George K. Abruzzo; Andrew M. Galgoci; Robert A. Giacobbe; Charles J. Gill; Ming Jo Hsu; Paul Liberator; Andrew S. Misura; Mary Motyl; Jennifer Nielsen Kahn; Maryann Powles; Fred Racine; Jasminka Dragovic; Weiming Fan; Robin Kirwan; Shu Lee; Hao Liu; Ahmed Mamai; Kingsley Nelson; Michael Peel

doi:10.1016/j.bmcl.2020.127661

Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor

James M. Apgar
, Robert R. Wilkening
, Dann L. Parker
, Dongfang Meng
, Kenneth J. Wildonger
, Donald Sperbeck
, Mark L. Greenlee
, James M. Balkovec
, Amy M. Flattery
, George K. Abruzzo
, Andrew M. Galgoci
, Robert A. Giacobbe
, Charles J. Gill
, Ming Jo Hsu
, Paul Liberator
, Andrew S. Misura
, Mary Motyl
, Jennifer Nielsen Kahn
, Maryann Powles
, Fred Racine

Jasminka Dragovic, Weiming Fan, Robin Kirwan, Shu Lee, Hao Liu, Ahmed Mamai, Kingsley Nelson, Michael Peel

Center for Discovery and Innovation

Hackensack Meridian School of Medicine

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

Abstract

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

Original language	English
Article number	127661
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	32
DOIs	https://doi.org/10.1016/j.bmcl.2020.127661
State	Published - Jan 15 2021

ASJC Scopus subject areas

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

Keywords

Enfumafungin
Ibrexafungerp
MK-3118
SCY-078
β-1,3-glucan synthesis inhibitor

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10.1016/j.bmcl.2020.127661

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Apgar, J. M., Wilkening, R. R., Parker, D. L., Meng, D., Wildonger, K. J., Sperbeck, D., Greenlee, M. L., Balkovec, J. M., Flattery, A. M., Abruzzo, G. K., Galgoci, A. M., Giacobbe, R. A., Gill, C. J., Hsu, M. J., Liberator, P., Misura, A. S., Motyl, M., Nielsen Kahn, J., Powles, M., ... Peel, M. (2021). Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor. Bioorganic and Medicinal Chemistry Letters, 32, Article 127661. https://doi.org/10.1016/j.bmcl.2020.127661

@article{e236041b51e14f37b4096c5ae788248d,

title = "Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor",

abstract = "We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.",

keywords = "Enfumafungin, Ibrexafungerp, MK-3118, SCY-078, β-1,3-glucan synthesis inhibitor",

author = "Apgar, \{James M.\} and Wilkening, \{Robert R.\} and Parker, \{Dann L.\} and Dongfang Meng and Wildonger, \{Kenneth J.\} and Donald Sperbeck and Greenlee, \{Mark L.\} and Balkovec, \{James M.\} and Flattery, \{Amy M.\} and Abruzzo, \{George K.\} and Galgoci, \{Andrew M.\} and Giacobbe, \{Robert A.\} and Gill, \{Charles J.\} and Hsu, \{Ming Jo\} and Paul Liberator and Misura, \{Andrew S.\} and Mary Motyl and \{Nielsen Kahn\}, Jennifer and Maryann Powles and Fred Racine and Jasminka Dragovic and Weiming Fan and Robin Kirwan and Shu Lee and Hao Liu and Ahmed Mamai and Kingsley Nelson and Michael Peel",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2021",

month = jan,

day = "15",

doi = "10.1016/j.bmcl.2020.127661",

language = "English",

volume = "32",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

}

Apgar, JM, Wilkening, RR, Parker, DL, Meng, D, Wildonger, KJ, Sperbeck, D, Greenlee, ML, Balkovec, JM, Flattery, AM, Abruzzo, GK, Galgoci, AM, Giacobbe, RA, Gill, CJ, Hsu, MJ, Liberator, P, Misura, AS, Motyl, M, Nielsen Kahn, J, Powles, M, Racine, F, Dragovic, J, Fan, W, Kirwan, R, Lee, S, Liu, H, Mamai, A, Nelson, K & Peel, M 2021, 'Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor', Bioorganic and Medicinal Chemistry Letters, vol. 32, 127661. https://doi.org/10.1016/j.bmcl.2020.127661

TY - JOUR

T1 - Ibrexafungerp

T2 - An orally active β-1,3-glucan synthesis inhibitor

AU - Apgar, James M.

AU - Wilkening, Robert R.

AU - Parker, Dann L.

AU - Meng, Dongfang

AU - Wildonger, Kenneth J.

AU - Sperbeck, Donald

AU - Greenlee, Mark L.

AU - Balkovec, James M.

AU - Flattery, Amy M.

AU - Abruzzo, George K.

AU - Galgoci, Andrew M.

AU - Giacobbe, Robert A.

AU - Gill, Charles J.

AU - Hsu, Ming Jo

AU - Liberator, Paul

AU - Misura, Andrew S.

AU - Motyl, Mary

AU - Nielsen Kahn, Jennifer

AU - Powles, Maryann

AU - Racine, Fred

AU - Dragovic, Jasminka

AU - Fan, Weiming

AU - Kirwan, Robin

AU - Lee, Shu

AU - Liu, Hao

AU - Mamai, Ahmed

AU - Nelson, Kingsley

AU - Peel, Michael

PY - 2021/1/15

Y1 - 2021/1/15

N2 - We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

AB - We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

KW - Enfumafungin

KW - Ibrexafungerp

KW - MK-3118

KW - SCY-078

KW - β-1,3-glucan synthesis inhibitor

UR - https://www.scopus.com/pages/publications/85097378783

U2 - 10.1016/j.bmcl.2020.127661

DO - 10.1016/j.bmcl.2020.127661

M3 - Article

C2 - 33160023

SN - 0960-894X

VL - 32

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 127661

ER -

Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor

Abstract

ASJC Scopus subject areas

Keywords

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