Tina Morwick

Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode.

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.

Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915).

The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.

Acetylide anions exert complete control over aldolization during the direct conversion of squarate esters into polyquinanes

Abstract The sequential condensation of diisopropyl squarate with a vinyl anion and a lithium acetylide triggers a cascade of mechanistic events that eventuates in formation of highly functionalized unsaturated diquinanes.

Addition of 2,3-dihydro-5-furanyllithium to diisopropyl squarate as a means for the rapid generation of structurally complex oxygen-containing tetraquinane networks

Abstract The ability of 2,3-dihydro-5-furanyllithium (11) to trigger a reaction cascade when added to diisopropyl squarate (6) has been examined. Of particular concern were those experiments in which greater than 2 equiv of 11 were added to 6, as well when 1 equiv of 11 was added prior to or after an equiv of cyclopentenyllithium. The results shed light directly on such issues as whether the second vinyl anion adds cis or trans in reference to the first, and whether the bonding takes place in 1,2 or 1,4 fashion. Also revealed in the unsymmetrical case studies was whether protonation of the 1,3,5-cyclooctatriene intermediates occurs syn or anti to the adjacent proton and the extent to which this materialized at the “conventional” or the oxygen-substituted enolate site. In light of the fact that heterocyclic tetraquinanes containing five stereogenic centers are directly elaborated in one step from achiral building blocks, the transformations described in this work can be justifiably classified as “power reactions”.

Hit to Lead Account of the Discovery of Bisbenzamide and Related Ureidobenzamide Inhibitors of Rho Kinase

A highly selective series of bisbenzamide inhibitors of Rho-associated coiled-coil forming protein kinase (ROCK) and a related ureidobenzamide series, both identified by high throughput screening (HTS), are described. Details of the hit validation and lead generation process, including structure-activity relationship (SAR) studies, a selectivity assessment, target-independent profiling (TIP) results, and an analysis of functional activity using a rat aortic ring assay are discussed.

Lithiation of trimethylsilyl substituted acetamide derivatives : Addition to carbonyl compounds

Abstract The lithio anions of N,O-bis(trimethylsilyl)acetamide and N-(trimethylsilyl)-N-methylacetamide were prepared and reacted with several carbonyl compounds to form β hydroxy acetamide and N-methylacetamide derivatives.