Corrections to Synthesis, Biological Evaluation, X-ray Structure, and Pharmacokinetics of Aminopyrimidine c-jun-N-terminal Kinase (JNK) Inhibitors

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

“…Following meticulous literature search using SciFinder (Di et al, 2013;Do et al, 2019;Kamenecka et al, 2010), we settled on structurally novel, 2-phenyl-substituted 4-amino-6,7-dihydro-5Hcyclopenta[d]pyrimidine scaffold (Figure 1) as the skeleton for the design and development of anti-GBM therapeutics, preferentially acting via relevant kinase inhibition modality, using GBM cell lines in preliminary phenotypic assays. To the best of our knowledge and understanding, this is the first report demonstrating the utility of this novel scaffold for hit discovery of anti-GBM therapeutics.…”

“…The 4amino substituent (preferably monosubstituted, i.e., R 2 = H) and the pyrimidine N3 (substructure highlighted in green, Figure 1) are hypothesized to interact with the kinase hinge residues, and help lead structures cross BBB (chemotype 7, Figure 1) due to the basic, relatively planar and lipophilic nature of the scaffold. Previous literature reports emphasized the importance of enhanced lipophilicity and rigidity of lead structures along with the basic nature of the scaffold, such as 2-aminopyrimidine (Di et al, 2013;Do et al, 2019;Kamenecka et al, 2010), contributing to the brain penetration and reducing the efflux transporter (e.g., P-glycoprotein, breast-cancer resistant protein) substrate liability. Such reports on 4aminopyrimidines are relatively scarce (Tsang et al, 2020).…”

“…stretch),1746 .23 (C=N stretch), 1644 .98, 1522 4-chloro-2-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(11) In a 100 mL round-bottom flask equipped with a reflux condenser and a calcium chloride guard-tube, a mixture of 10 (2.122 g, 10 mmol) and POCl 3 (15 mL) was stirred and refluxed for 2 h. After cooling to T A B L E 2 Relevant molecular, physicochemical, and biopharmaceutical property value ranges for the designs F 1 −F 20 .Serial noProperty, a(Do et al, 2019;Di et al, 2013;Kamenecka et al, 2010) a Calculated using SwissADME.RT, the resultant crude mixture was poured in crushed ice (15 g) and neutralized with sat. NaHCO 3 solution.…”