A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes

A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

“…Comparing the butyloxycarbonyl sulfonamide 85 , one of the most metabolically unstable compounds in this report, with the corresponding ethoxycarbonyl compound 88 reveals only a slightly improved stability in mouse liver microsomes for the latter. A larger increase was expected in accordance with previously reported data . A larger impact on stability in human microsomes with a shortened carbamate alkyl chain can be noted when comparing 86 and with 90 .…”

“…As we have reported on previously, affinity to human AT 2 R expressed in HEK‐293 cells for C38 is reduced as compared to affinity for AT 2 R in pig uterus membrane (270 nM vs 19 nM) ,. When evaluating affinity of the previously published, and very promising, amides C93 , C97 , and C102 (Table ) for human AT 2 R in HEK‐293 cells we note a slight decrease in affinity for compound C93 (110 nM in human AT 2 R vs 29 nM in pig AT 2 R).…”

“…Comparing compound 90 and compound 86 , a slight decrease in affinity could also be detected with the shorter carbamate chain (120 nM vs 56 nM). This indicates the length of the sulfonyl carbamate chain may be more significant in the bicyclic scaffold than in the C38 ‐scaffold, where our previous studies showed a large tolerability in this moiety . The cyclopropane carboxamide 91 had a similar affinity as the amides C93 / C97 and the bicyclic amide 90 .…”

“…Previous work from our group demonstrated that the affinity and selectivity of the ligands can be retained by replacing the imidazole with amides; with these new bicyclic amides we continue our exploration of the promising amide functionality by trying to ascertain the binding conformation. A majority of the bicyclic compounds retained a shortened sulfonyl carbamate chain, as we have recently found this to be beneficial for metabolic stability . The key building block for the synthesis of both series was MIDA boronate 3 , that was synthesized according to the pathway previously published by our group .…”

“…A majority of the bicyclic compounds retained a shortened sulfonyl carbamate chain, as we have recently found this to be beneficial for metabolic stability . The key building block for the synthesis of both series was MIDA boronate 3 , that was synthesized according to the pathway previously published by our group . Microwave assisted Negishi coupling in a sealed vial of 5‐bromo‐ N ‐( tert ‐butyl)thiophene‐2‐sulfonamide ( 1 ) ] with in situ generated isobutylzinc chloride produced N ‐( tert ‐butyl)‐5‐isobutylthiophene‐2‐sulfonamide ( 2 ) in 51 % yield ,.…”