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 physicochemical profile.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…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.…”

Lipoprotein‐associated phospholipase A2: The story continues

“…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.…”

“…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 …”

“…Recent studies reported that a bicyclo[1.1.1]pentane moiety replacement of a phenyl ring in darapladib and rilapladib maintained inhibitory potency and displayed improved physicochemical properties compared to their respective parent compounds. This substitution resulted in improved solubility and an enhanced overall PK profile …”

“…The crystal structure of bioisosteric analog 2 in the Lp-PLA2 protein was solved at 1.9 Å resolution and revealed a binding precludes the adjacent trifluorophenyl moiety extending as far toward Leu121 and Phe125, while showing no effect on the main interactions within the oxyanion hole. 68 Currently, FBLD has gradually matured to be a reliable and efficient approach for producing promising lead compounds for subsequent medicinal chemistry optimization, and more than 30 drug candidates derived from fragments have entered in clinical trials. 69 On the basis of the aforementioned crystal structures, both Astex in collaboration with GSK and our group applied the FBLD strategy to identify novel Lp-PLA2 inhibitors, consequently releasing numerous crystal structures for fragment hits or representative compounds.…”