2016
DOI: 10.1021/acsmedchemlett.6b00281
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Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

Abstract: We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA 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 … Show more

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Cited by 171 publications
(133 citation statements)
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“…But, unfortunately, the inhibitor has a suboptimal physicochemical profile, with a high molecular weight, low aqueous solubility, and high property forecast indices (PFI); a risk indicator of developability . But through the substitution of the suboptimal benzene ring with a BCP moiety 283 a , the PK profile of the drug was improved while maintaining potency . This drug was synthesized over a number of steps, the key transformation involved a dichlorocarbene insertion into a bicyclo[1.1.0]butane system.…”
Section: Application Of Rigid‐linear Linkers In Small Molecule Drugsmentioning
confidence: 99%
“…But, unfortunately, the inhibitor has a suboptimal physicochemical profile, with a high molecular weight, low aqueous solubility, and high property forecast indices (PFI); a risk indicator of developability . But through the substitution of the suboptimal benzene ring with a BCP moiety 283 a , the PK profile of the drug was improved while maintaining potency . This drug was synthesized over a number of steps, the key transformation involved a dichlorocarbene insertion into a bicyclo[1.1.0]butane system.…”
Section: Application Of Rigid‐linear Linkers In Small Molecule Drugsmentioning
confidence: 99%
“…This substitution resulted in improved solubility and an enhanced overall PK profile. 68 However, although darapladib can be used orally, it displayed poor plasma exposure (data from GSK 238 and our group 244 ), probably owing to its high molecular weight and strong lipophilicity (MW = 667, clogP = 8.3). Since 2012, F I G U R E 9 The discovery of darapladib and rilapladib.…”
Section: Pyrimidone Derivativesmentioning
confidence: 83%
“…The crystal structure of bioisosteric analog 2 in the Lp‐PLA2 protein was solved at 1.9 Å resolution and revealed a binding mode similar to that of darapladib. The replacement of the phenyl ring with a bicyclo[1.1.1]pentane moiety slightly precludes the adjacent trifluorophenyl moiety extending as far toward Leu121 and Phe125, while showing no effect on the main interactions within the oxyanion hole …”
Section: Biochemical Properties and Structural Characteristicsmentioning
confidence: 99%
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