Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches

“…In a subsequent paper, further SAR was described, showing limited impact on PXR activation and highlighting the challenges inherent within this series to balance primary potency and PK and CNS penetration with PXR activation . SAR investigations of the chloro-phenyl ring identified the difluoro-substitution exemplified by 244 as optimal; however, PXR activity was still an issue, Figure .…”

“…In a subsequent paper, further SAR was described, showing limited impact on PXR activation and highlighting the challenges inherent within this series to balance primary potency and PK and CNS penetration with PXR activation. 236 SAR investigations of the chloro-phenyl ring identified the difluoro-substitution exemplified by 244 as optimal; however, PXR activity was still an issue, Figure 67. Changing the trifluoroethyl group to difluoroethyl made minimal impact (245, Figure 67) but resulted in a compound that was further profiled in vivo due to the optimal balance of other properties.…”

Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base

“…Merck 11 was interested in the synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2 (1H)-ones as novel non-nucleoside HIV-1 reverse-transcriptase inhibitors. Modification at the 3-and 4-positions of the quinazolinone ring by different substituents afforded potent and selective T-type calcium channel antagonist 12,13 that displayed in vivo central nervous system efficacy in epilepsy and tremor models. 14 Furthermore these antagonists are attracting a lot of interest for the treatment of peripheral and central nervous system (CNS) disorders 15 or as effective agents for pain therapies.…”

Microwave-Assisted aza-Friedel–Crafts Arylation of N-Acyliminium Ions: Expedient Access to 4-Aryl 3,4-Dihydroquinazolinones

“…8−11 The C4-substituted quinazolinone framework is known to exhibit a wide range of biological properties. For example, SM-15811 is a potent Na + /Ca 2+ exchanger inhibitor, 12−14 proquazone is an anti-inflammatory drug, 15,16 and 4-disubstituted 3,4-dihydroquinazolinones are T-type channel selective calcium blockers with in vivo central nervous system efficacy in epilepsy and tremor models 17,18 (Figure 1). Finally, the 3,4-dihydroquinazolinones DPC 961 and DPC 083 and related analogs are potent human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors.…”

“…In particular, in situ-generated N -acyliminium ions have been widely exploited in the synthesis of bioactive nitrogen-containing heterocycles, especially in the preparation of alkaloid natural products. ,,, Accordingly, the development of rapid, convenient, and high-yielding protocols for the selective intra- or intermolecular nucleophilic addition to cyclic N -acyliminium ions remains a field of considerable interest. − The C4-substituted quinazolinone framework is known to exhibit a wide range of biological properties. For example, SM-15811 is a potent Na + /Ca 2+ exchanger inhibitor, − proquazone is an anti-inflammatory drug, , and 4-disubstituted 3,4-dihydroquinazolinones are T-type channel selective calcium blockers with in vivo central nervous system efficacy in epilepsy and tremor models , (Figure ). Finally, the 3,4-dihydroquinazolinones DPC 961 and DPC 083 and related analogs are potent human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors. , …”