New R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (±)-cromakalim as tissue-selective pancreatic β-cell KATP channel openers

Direct Activation ofβ-Cell KATPChannels with a Novel Xanthine Derivative

“…Clinical trials were initiated but later suspended due to druginduced elevations of key liver enzymes (Hansen, 2006). Analogs of the SUR2-preferring openers cromakalim and pinacidil that exhibit selectivity for pancreatic K ATP channels (Khelili et al, 2006(Khelili et al, , 2008Sebille et al, 2006Sebille et al, , 2008Florence et al, 2009Florence et al, , 2011 have also been developed, showing that it is possible to switch SUR preference with chemical modifications to the scaffold. To our knowledge, the only unique pancreatic K ATP channel activator chemotypes reported in the last 2 decades were identified in screens of small-molecule libraries.…”

N-Aryl-N′-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis

“…After careful examination, however, some discrepancies were noticed with respect to the nature and the position (ortho, meta, or para) of the substituent on the phenyl ring of arylureas and arylthioureas. Indeed, methoxy-substituted compounds were found to be less active on b-cells as well as on glioma cells than chloro-, cyano-, and nitro-substituted compounds [17,18]. However, chloro-, cyano-, and nitro-substituted compounds were almost equally effective on b-cells [17,18], while the rank order of potency on glioma cells appeared to be nitro-> cyano-> chloro-compounds (Table 3).…”

“…Indeed, methoxy-substituted compounds were found to be less active on b-cells as well as on glioma cells than chloro-, cyano-, and nitro-substituted compounds [17,18]. However, chloro-, cyano-, and nitro-substituted compounds were almost equally effective on b-cells [17,18], while the rank order of potency on glioma cells appeared to be nitro-> cyano-> chloro-compounds (Table 3). Moreover, looking at the chloro-compounds in the arylurea-type chroman series, although the ortho position was less favorable for activity on pancreatic b-cells [16,17], no clear differences were found between ortho-, meta-, and para-substituted chloro-compounds for growth inhibitory activity on glioma cells (Table 3).…”

“…However, chloro-, cyano-, and nitro-substituted compounds were almost equally effective on b-cells [17,18], while the rank order of potency on glioma cells appeared to be nitro-> cyano-> chloro-compounds (Table 3). Moreover, looking at the chloro-compounds in the arylurea-type chroman series, although the ortho position was less favorable for activity on pancreatic b-cells [16,17], no clear differences were found between ortho-, meta-, and para-substituted chloro-compounds for growth inhibitory activity on glioma cells (Table 3). To confirm or refute the possible link between the K ATP -channelopening potency of drugs and their growth inhibitory activity, we tested several reference compounds known to be K ATP -channel openers or blockers.…”

Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

“…Figure 1. [18][19][20][21][22][23][24][25][26] Figure1 illustrates examples of typical 2,2-dimethylchromans developed by our research group. secretory process may also be observed with drugs targeting the L-type voltage-operated calcium channels.…”