Femoral Revision with an Extensively Hydroxyapatite-Coated Femoral Component

Between December 1996 and April 2003, 26 consecutive femoral component revisions in 24 patients were performed with an extensively hydroxyapatite-coated femoral stem. Two patients were lost to follow-up, and two patients died of unrelated causes. Of the 22 femoral revisions in 20 patients, there was a 0% incidence of mechanical loosening at average follow-up of 3.2 years (2–6.3 years). The Harris Hip Score improved from 59 (36 to 83) to 95 (84 to 100) postoperatively (p < 0.001). Rate of revision was 18.2% (4.5% for sepsis, 9.1% for instability, and 4.5% for polyethelene wear). All 22 femoral components had evidence of bone ingrowth. The extensively coated hydroxyapatite stem in this series produced excellent clinical results with a low incidence of thigh pain (4.5%) and severe stress shielding (4.5%)

Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)

We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as <b>63</b> exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug–target residence time was determined via SPR. Analysis of these data suggests that drug–target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target

Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)

We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as <b>63</b> exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug–target residence time was determined via SPR. Analysis of these data suggests that drug–target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target