Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors

Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

“…Although the cinnoline variants [141] were potent LRRK2 inhibitors (wt IC 50 ¼ 7 nM), they were found to be promiscuous in a small kinase panel. By focusing the core to quinoline [138], e.g., 43, kinase selectivity was significantly improved and in vivo activity was demonstrated (CNS MPO ¼ 5.05). One final variation of the 6,5-fused ring system is illustrated by 32.…”

“…Strategies to mitigate crossover to TTK, which has an Asp residue in this position, have included the introduction of small groups that would cause unfavorable steric and/or electrostatic interactions with the Asp side chain [132,133,135]. Selectivity of a series of 7-aryl-substituted quinoline derivatives may also be due to the placement of polar groups in the vicinity of the unconserved S1954 and R1957 residues [138]. Interactions with the unconserved R1957 and H1998 LRRK2 residues may also contribute to selectivity in a series of indolinone compounds [144].…”

“…There is no consensus on a "best" template to build LRRK2 kinase domain homology models due to the fact that the kinases for which X-ray crystal structures have been published have at most 30% sequence identity to LRRK2. The most common templates have been from B-Raf [94,101,[129][130][131], JAK-2 [132][133][134][135][136][137][138], MLK1 [132,[136][137][138][139], ROCO4 [131,140], and TAK1 [132,141,142] kinases, chosen based on overall kinase sequence identity, ATP-binding site identity, and/or crossover of inhibitor activity. Consensus from these alignments is that G2019 is the Gly in the conserved DFG motif (DYG in LRRK2) and I2020 is the subsequent residue in the activation loop (Fig.…”

Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking

“…3) 37 from experimental screening of a focused library of known kinase inhibitors and about 250 negative decoys assembled from random vendor molecules and known non-binders. [38][39][40][41][42][43][44] For the positive examples, fifty low energy conformers were generated for each molecule and for the negative examples, five low energy conformers were generated per molecule. Next, the pharmacophoric points were extracted in 3D space and the pharmacophore constellations were clustered.…”

Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor

“…14,15 The pyrrolopyrimidine PF-06447475 (7) 16 was recently reported to also be a potent and selective LRRK2 inhibitor capable of reducing LRRK2 activity in the brain of G2019S LRRK2 transgenic mice after oral dosing. Additional ATP-competitive LRRK2 inhibitors that have been reported include cinnolines, 17 triazolopyridazines, 18 and 3-cyanoquinazolines, 19 as well as several others that have appeared in the patent literature. 20−24 Based on the chemical structure of GNE7915 (6), we thought intramolecular hydrogen bonding was likely to exist between the C-5 trifluoromethyl group and the NH hydrogen to give the pseudobicycle shown in Figure 1.…”