David Anthony Roberts

A synthesis of 2- and 4(5)-(2-pyridinyl)imidazoles by palladium-catalysed cross-coupling reactions

Abstract N-Substituted imidazolylzinc chlorides were reacted with 2-bromopyridine in the presence of Pd(PPh3)4 and a two-fold excess of ZnCl2 to afford cross-coupled products in 58–93% yields. Deprotection provided convenient routes to 2- or 4(5)-(2-pyridinyl)imidazoles.

Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).

Quinoline, 1,5-naphthyridine and pyridine derivatives as potent, nonpeptidic angiotensin II receptor antagonists

Abstract Quinoline-, 1,5-naphthyridine- and pyridine-based angiotensin II antagonists are reported. The more potent compounds gave IC 50 values of ca 0.01 μM in a guinea pig adrenal membrane binding assay and intravenous ED 50 values in the range 0.1–1.0 mg/kg for inhibition of the AII-induced pressor response in normotensive rats. Several of these compounds, for example 4d (ICI D6888), showed good oral activity in this animal model.

The synthesis and biological activity of tetrahydroquinoline angiotensin II antagonists containing a substituted biphenyltetrazole group

Abstract The synthesis of analogues of tetrahydroquinoline angiotensin II antagonist, ZENECA ZD6888, bearing substituents on the biphenyl ring system is reported. Several of these compounds show comparable or superior activity to ZD6888 in an in vitro beinding assay and in inhibition of the AII-induced pressor response in normotensive rats.