ml500433j_si_001.pdf (206.75 kB)
Structural Insights for the Optimization of Dihydropyrimidin-2(1H)‑one Based mPGES‑1 Inhibitors
journal contributionposted on 2015-02-12, 00:00 authored by Stefania Terracciano, Gianluigi Lauro, Maria Strocchia, Katrin Fischer, Oliver Werz, Raffaele Riccio, Ines Bruno, Giuseppe Bifulco
The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors.