Fragment-Based Discovery of Pyrimido[1,2-<i>b</i>]indazole PDE10A Inhibitors

Abstract

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Indoleninyl-substituted pyrimido[1,2-b]indazoles via a facile condensation reaction

“…Pyrimido[1,2- b ]indazoles are a class of fused nitrogen-containing tricyclic skeletons that have received significant attention as pharmacologically important molecules, e.g. as anti-cancer agents, 1 monoamine oxidase (MAO) inhibitors, 2 PDE10A inhibitors, 3 and for the treatment of hepatitis C virus (HCV) infection. 4 Despite their high bioactive potential, the preparation of pyrimido[1,2- b ]indazoles is rarely documented due to the limited synthetic options and strategies.…”

Synthesis of Substituted Pyrimido[1,2‐b]indazoles through (3+2+1) Cyclization of 3‐Aminoindazoles, Ketones, and N,N‐Dimethylaminoethanol as One‐Carbon Synthon

“…Fused nitrogen‐containing aromatic compounds occur widely in pharmaceuticals, agrochemicals, natural products, and material science [1] . Pyrimido[1,2‐ b ]indazoles are aza‐fused tricylic compounds, which exhibit remarkable photophysical properties [2] and good biological activities such as anticancer, [3] anti‐bacterial, [4] and anti‐MAO‐B [5] activity and inhibition of phosphodiesterase10A (PDE10A) [6] . Despite their multiple efficacies, little effort has been devoted to constructing this tricyclic framework.…”

“…[1] Pyrimido [1,2b]indazoles are aza-fused tricylic compounds, which exhibit remarkable photophysical properties [2] and good biological activities such as anticancer, [3] antibacterial, [4] and anti-MAO-B [5] activity and inhibition of phosphodiesterase10A (PDE10A). [6] Despite their multiple efficacies, little effort has been devoted to constructing this tricyclic framework. Condensation of 3-aminoindazoles with carbonyl molecules has been the most common approach for the synthesis of substituted pyrimido [1,2-b]indazoles.…”

I2-Promoted gem-Diarylethene Involved Aza-Diels–Alder Reaction and Wagner–Meerwein Rearrangement: Construction of 2,3,4-Trisubstituted Pyrimido[1,2-b]indazole Skeletons

“…Polycyclic nitrogen heterocyclic skeletons occur widely in both natural compounds and synthetic drugs . In particular, pyrimido­[1,2- b ]­indazoles, comprising nitrogen-rich fused-ring structures, exhibit significant activity against several diseases and also have interesting photophysical properties .…”