Timothy F. Gallagher

SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1

A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739–746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC50 = 0.6 μM), suppresses the activation of MAPKAP kinase‐2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin‐1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase‐2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase‐2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase‐2.

Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity.

Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole inhibitors of p38 kinase is reported. Oral administration of inhibitors possessing a cyclohexan-4-ol or piperidin-4-yl group at N-1 in combination with alkoxy, amino(alkyl), phenoxy and anilino substitution at the 2-position of the pyrimidine was found to potently inhibit LPS-induced TNF in mice and rats. The selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580.

Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375

1 SB‐706375 potently inhibited [125I]hU‐II binding to both mammalian recombinant and ‘native’ UT receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT receptors and Ki 5.4±0.4 nM at the endogenous UT receptor in SJRH30 cells). 2 Prior exposure to SB‐706375 (1 μM, 30 min) did not alter [125I]hU‐II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action. 3 The novel, nonpeptidic radioligand [3H]SB‐657510, a close analogue of SB‐706375, bound to the monkey UT receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U‐II isopeptides and SB‐706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U‐II ligands sharing a common UT receptor binding domain. 4 SB‐706375 was a potent, competitive hU‐II antagonist across species with pKb 7.29–8.00 in HEK293‐UT receptor cells (inhibition of [Ca2+]i‐mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB‐706375 also reversed tone established in the rat aorta by prior exposure to hU‐II (Kapp∼20 nM). 5 SB‐706375 was a selective U‐II antagonist with 100‐fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin‐1 were unaltered by SB‐706375 (1 μM). 6 In summary, SB‐706375 is a high‐affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross‐species activity that will assist in delineating the pathophysiological actions of U‐II in mammals.

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.

Phenoxypyrimidine inhibitors of p38α kinase: synthesis and statistical evaluation of the p38 inhibitory potencies of a series of 1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl) imidazoles

As a continuation of our work with 1,4,5 substituted imidazole inhibitors of p38alpha, we report a series of 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl) imidazoles related to 7. The compounds have IC50s for inhibition of p38alpha ranging from 6.0 to 650nM. Statistical analysis of the p38beta inhibitor potencies shows a correlation of IC50s with the electron donating strength of low molecular weight substituents.

Acylprolinamides: a new class of peptide deformylase inhibitors with in vivo antibacterial activity.

A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.