Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor

Nicholas Measom; Kenneth D. Down; David J. Hirst; Craig Jamieson; Eric S. Manas; Vipulkumar K. Patel; Donald O. Somers

doi:10.1021/acsmedchemlett.6b00281

Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor

Nicholas Measom, Kenneth D. Down, David J. Hirst, Craig Jamieson, Eric S. Manas, Vipulkumar K. Patel, Donald O. Somers

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Abstract

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

Original language	English
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	7
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00281
Publication status	Published - 15 Nov 2016

Keywords

LpPLA2
bicyclo[1.1.1]pentane
bioisostere
darapladib
cardiovascular disease
physicochemical
bioisosteric phenyl replacements

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10.1021/acsmedchemlett.6b00281

Measom-etal-ACSMCL2016-bicyclo[1.1.1]pentane-as-a-phenyl-replacement-within-an-LpPLA2-inhibitorAccepted author manuscript, 1.2 MB

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abstract = "We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.",

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T1 - Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor

AU - Measom, Nicholas

AU - Down, Kenneth D.

AU - Hirst, David J.

AU - Jamieson, Craig

AU - Manas, Eric S.

AU - Patel, Vipulkumar K.

AU - Somers, Donald O.

PY - 2016/11/15

Y1 - 2016/11/15

N2 - We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

AB - We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

KW - LpPLA2

KW - bicyclo[1.1.1]pentane

KW - bioisostere

KW - darapladib

KW - cardiovascular disease

KW - physicochemical

KW - bioisosteric phenyl replacements

UR - http://pubs.acs.org/journal/amclct

U2 - 10.1021/acsmedchemlett.6b00281

DO - 10.1021/acsmedchemlett.6b00281

M3 - Article

VL - 7

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

ER -

Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor

Abstract

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