N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands.

Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tert-butylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An ATR selective ligand with a K of 42 nM was identified in the first series and in the second series, six ATR selective ligands with significantly improved binding affinities and K values of <5 nM were discovered. The binding modes to ATR were explored by docking calculations combined with molecular dynamics simulations.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow.

Convergent Total Synthesis of (-)-Cyclopamine.

A concise and enantioselective total synthesis of the alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a synthesis of the -6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.

Overcoming Limitations in Decarboxylative Arylation via Ag-Ni Electrocatalysis.

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO, proceeding at room temperature with a simple commercial potentiostat.

2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands.

Ligands comprising a benzimidazole rather than the imidazole ring that is common in ATR ligands e.g. in the ATR agonist C21, can provide both high affinity and receptor selectivity.

Angiotensin II AT2 receptor ligands with phenylthiazole scaffolds.

The syntheses and the ATR and ATR binding data of a series of new small molecule ligands are reported. These ligands comprise a phenylthiazole scaffold rather than the biphenyl or phenylthiophene scaffolds found in essentially all of the previously described ligands originating from the nonselective ATR/ATR ligand L-162,313 and the ATR selective agonist C21, the latter now in Phase II/III clinical trials. A phenylthiazole rather than the phenylthiophene scaffold that is present in the ATR selective agonist C21 and in the ATR selective antagonist C38 had a deleterious effect on the affinity to ATR.