Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-yl)benzamide. Structure-Activity Relationship and Preclinical Characterization.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Judet osteoperiosteal decortication for treatment of non-union: the Cornwall experience.

BACKGROUND: The treatment of non union can be challenging with a variety of surgical options available to achieve bone consolidation. Robert Judet first described a method of osteo-periosteal decortication in 1963. He stated that by elevating cortical chips that remain attached to the periosteum and overlying soft tissues surrounding the site of non-union, combined with mechanical support, the bone consolidated. Despite excellent results presented in 2008 of 99% union rates with a mean delay of 8 months, the technique has not yet become popularised. We aim to show that Judet's method of decortication can achieve good results in the management of failure of union in a hospital other than Judet's. METHODS: Retrospective analysis was performed from December 2002 to December 2008 of 40 cases in 39 patients of osteoperiosteal decortication for fracture non-union. Concurrent stabilisation was with internal fixation only. All procedures were performed by one surgeon (MN) using the Judet technique after learning the technique in the originators hospital. A preoperative non union scoring system was also used to assess its use in predicting persistent non-union. RESULTS: Union was successfully achieved in 36 of the 39 surviving cases (92.3%) after a median delay of 8 months (range 3-47, SD 9.2) Twenty-six patients (65%) achieved union following the decortication procedure without subsequent operations. Factors such as open fracture and smoking did not have a statistically significant effect on union. The mean number of procedures following decortication was 0.68 (range 0-4). Metalwork failure occurred in 11 cases (28%), the majority in femoral decortications (n=9, 82%). The femur was the site of all persistent non unions in the series. Three patients had superficial infections and two had deep infections. The pre-operative non union scoring system (0-100) means were noticeably worse for the persistent non union group 42.0 (20-46) compared with the union group 31.0 (range 4-52). CONCLUSIONS: Osteoperiosteal decortication remains a highly effective surgical technique in the management of failed fracture union. The non union scoring system is a reliable predictor of persistent non union after this type of surgery. CLINICAL RELEVANCE: Relevant to general trauma orthopaedic surgeon and specialist orthopaedic surgeons with an interest in fracture non-union.