Search

HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.

Increasing evidence suggests that interactions between tumor cells, stromal cells, macrophages and the extracellular matrix are pivotal to the processes of tumorigenesis, metastasis, and neovascularization. Macrophages within the tumor microenvironment are thought to facilitate cancer progression, making them intriguing targets for therapy. Colony stimulating factor 1 (CSF-1) and its receptor, cFMS, play a central role in the development of mononuclear phagocytes, recruitment of macrophages to tumors, and differentiation and function of osteoclasts. We have developed an orally active, selective small-molecule cFMS inhibitor for cFMS. This molecule inhibits cFMS cellular activity (IC50 = 9 nM) in vitro and inhibits cFMS phosphorylation in a transfected cell line grown in nude mice (ED50 = 3 mg/kg). Our compound also inhibits CSF-1-mediated osteoclast differentiation and function (IC50 values of = 4 nM and 58 nM, respectively). To further explore the potential of our selective inhibitor for the treatment of cancer, we evaluated anti-tumor activity in several preclinical models. We first explored the effect on the murine ovarian cancer cell line, ID8. ID8 cells injected intraperitoneally into nude mice form multiple peritoneal tumor deposits and abundant ascites. Macrophage infiltration in the ID8 ascites was markedly lowered in mice treated with a cFMS inhibitor. Using MCF-7, a human breast adenocarcinoma cell line that has been shown to produce M-CSF, a daily oral dose with 100 mg/kg of our inhibitor for 21 days significantly reduced tumor growth and was accompanied by a marked reduction in tumor-associated macrophages. These findings support the potential of a selective inhibitor of cFMS to favorably impact human cancers by modulating tumor-associated macrophage functions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2011-551