Synthesis and evaluation of diphenylphosphinic amides and diphenylphosphine oxides as inhibitors of Kv1.5

Copper‐Catalyzed (Di)Arylmethylation of Phosphorylamides Under Oxidative Conditions

“…Phosphonamides and phosphinamides, which are generally called phosphorylamides, have drawn widespread research interests for the exceptional structures and broad applications in the communities of clinical explorations and material science Furthermore, chiral P(O)–N‐cored motifs have been prepared for asymmetric syntheses, and novel methodologies have been developed from the flexible molecules toward some biologically active heterocycles in the presence of different transition metallic catalysts . Despite that rapid growth in the field has been wittnessed, the topic remained underexploited because of the fragilities of the P–N bonds and unusually stable N–H bonds to other amides, meaning the direct N ‐functionalization of the amides with the reservation of the P–N bonds remained a great challenge up to date. On the other hand, new transformations are still severely desired for the improvement of the diversity of phosporylamides.…”

“…Benzylation has called our attention for the recent report on the methylation/alkylation of phosphorylamides [Scheme , Equation (1)]. Traditional means of benzylic functionalization involving preactivated substrates suffer from harsh conditions and tedious steps and generation of halogenated waste products amongst other issues , . However, benzylic C–H bonds, which are highly reactive, have been directly oxidized to construct different C(sp 3 )–N bonds because direct functionalization is more environmentally friendly and atom/step economical.…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…The compound 85 was well tolerated in rabbits with no signs of the CNS-like side effects observed for other Kv1.5 blockers (Figure 24). Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC 50 of 0.08 µM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23).…”

“…However, both hERG and IKs active and remarkable safety in rats of compound 83 was detected and judged unsuitable for in vivo testing; conversely, the derivative 84 was regarded as a hopeful compound for further development with Kv1.5 IC 50 , IKs, C eu20 , and QT max change values for 1.0 µM, >33%, 0.6 µM, and <10%, respectively. Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC50 of 0.08 μM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23).…”

Catalytic Asymmetric Hydrophosphination of ortho-Quinone Methides

“…ortho -Quinone methides ( o -QMs), a type of highly reactive and versatile synthetic intermediate, can participate in a variety of catalytic asymmetric conjugate additions and [4 + 2] cycloadditions. , In light of this, we envisioned that employing o -QMs in an asymmetric hydrophosphination reaction would provide a convenient and enantioselective way to build C–P bonds, providing chiral α-arylmethyl phosphine oxides that might serve as bioactive pharmaceutical intermediates . Interestingly, although catalytic asymmetric conjugate additions of o -QMs and aza- o -QMs using carbon, oxygen, sulfur, , and nitrogen nucleophiles have been extensively explored, the corresponding reaction with a phosphorus nucleophile is still missing (Scheme ).…”