Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.

The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl(3) solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6-311G** and 6-311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified.

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.

The anthracycline antibiotics daunorubicin and doxorubicin have been used widely as anticancer drugs, but their cardiotoxicity limits their clinical use. We describe here the preparation of a small panel of daunorubicin analogues in which the anthraquinone core is replaced with simpler aromatic moieties that lack a quinone functionality. The targets consist of a functionalized 1,2,3,4-tetrahydro-naphthalene or 1,2,3,4-tetrahydro-anthracene core bound to one of three monosaccharides: daunosamine, acosamine, or 4-amino-2,3,6-trideoxy-L-threo-hexopyranose. Key steps in the synthesis included an enantioselective ring opening of benzo-fused norbornene derivatives for the preparation of the core structures and the use of silver hexafluorophosphate-promoted thioglycoside activation in the glycosylation of these cores. Evaluation of these compounds against the MCF-7 cancer cell line demonstrated that the identity of the carbohydrate moiety appeared to have little influence on the cytotoxicity. Moreover, the analogues with the 1,2,3,4-tetrahydro-naphthalene core showed no cytotoxicity, while those possessing the 1,2,3,4-tetrahydro-anthracene moiety were more active. The IC50 values for the latter group of compounds were in the range of 94-134 mu M, compared to 17 mu M for doxorubicin and 5 mu M for daunorubicin.

In the title compound, C 29 H 34 O 2 Si, the isopropenyl group is oriented trans and the OH group is cis to the tert -butyl­diphenyl­siloxy (OTBDPS) group. The cyclo­hexane ring of the tetra­hydro­naphthalene system adopts a half-chair conformation in which the stereogenic centre at the ring C3 atom is projected above the plane of the ring ( 3 H 2 ), minimizing steric congestion between the substituents on the ring C3 atom and the bulky OTBDPS group.

In the title compound, C29H34O2Si, the isopropenyl group is oriented trans and the OH group is cis to the tert-butyldiphenylsiloxy (OTBDPS) group. The cyclohexane ring of the tetrahydronaphthalene system adopts a half-chair conformation in which the stereogenic centre at the ring C3 atom is projected above the plane of the ring (H-3(2)), minimizing steric congestion between the substituents on the ring C3 atom and the bulky OTBDPS group.