Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

“…Although little attention has been given to further advancing orthosteric M 4 agonists, the drug development division of Sumitomo Dainippon Pharma in Japan published recent progress in developing dual M 1 /M 4 agonists (akin to Xanomeline) via the identification of scaffolds through HTS that were then coupled with known pharmacophores of M 4 PAMs and hybridized to discover lead compounds. Through their rather extensive SAR efforts, novel, highly selective M 1 /M 4 agonists based on N-substituted oxindole (blue, 7, Figure 5 ) [ 178 ], dihydroquinazolinone (green, 8, Figure 5 ) [ 179 ], and 7-azaindoline (red, 9, Figure 5 ) [ 180 ] were developed and evaluated in vitro. Compound 7 partially activated M 1 (EC 50 = 12 nM) and M 4 (EC 50 = 29 nM) while showing negligible off-target binding and potent CNS penetration.…”

2,3-Dihydroquinazolin-4(1H)-one as a privileged scaffold in drug design

“…3-(2-Oxoindolin-3-yl) DHQ derivatives showed antiproliferative activity against human tumor cell lines (IC 50 in the micromolar range). 322 Other 3-aryl and 3-alkyl DHQs also showed antitumor properties, inhibiting p38 MAP kinase, 323 and inosine 5 0monophospate dehydrogenase type II (IMPDH II). 324 The less studied 1,3-disubstituted DHQs could be obtained in two different ways: through the cyclization of N-substituted isatoic anhydride and substituted arylidene anilines, 299 or the reaction of 3-substituted DHQ with chloride (Scheme 15).…”

Discovery and Development of Muscarinic Acetylcholine M₄ Activators as Promising Therapeutic Agents for CNS Diseases

“…24 28) As expected, M 4 mAChR activators have also been found to possess antipsychotic effects in behavioral tests for psychosis. These compounds reversed psychostimulant-or NMDA receptor antagonist-induced locomotor hyperactivity, as well as psychostimulant-induced disruption of PPI [29][30][31][32][33][34][35][36][37][38] in rodents. In a rat electroencephalogram study, the M 4 mAChR positive allosteric modulator (PAM) VU0467154, like clozapine, reversed MK-801-induced elevations in high frequency gamma power, which is consistent with their antipsychotic activities.…”

“…Finally, compound 9 exhibited potent CNS penetration (brain/blood ratio=2.0) in rats. 30) In addition to the discovery of an M 4 mAChR partial agonist, dihydroquinazolinone derivatives were identified as selective M 1 full and M 4 mAChRs partial agonists (compound 10; M 1 : 81%, M 2 : 1%, M 3 : 2%, M 4 : 49% at 0.3 µM, M 5 : 3% at 30 µM) 31) (Fig. 6).…”