[3<i>a</i>,4]-Dihydropyrazolo[1,5<i>a</i>]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

A series of novel [3<i>a</i>,4]­dihydropyrazolo­[1,5<i>a</i>]­pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R₃) and back-pocket (R₄) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered through X‑ray Fragment Screening

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA₂) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA₂ in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered through X‑ray Fragment Screening

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA₂) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA₂ in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues