L'invention concerne des composes de formule (I) : dans laquelle les variables sont definies ici. L'invention concerne egalement des compositions pharmaceutiques de ceux-ci. Dans certains aspects, les composes et les compositions de la presente invention peuvent etre utilises comme modulateurs antioxydants de l'inflammation. Dans certains aspects, la presente invention concerne des procedes dans lesquels les composes et la composition decrits ici sont utilises pour le traitement de maladies et de troubles associes a l'inflammation et au cancer.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

La presente invention concerne de nouveaux modulateurs d'inflammation antioxydants, comprenant ceux de formule : (I), dans laquelle les variables sont definies dans la presente description. La presente invention concerne en outre des compositions pharmaceutiques, des trousses et des articles de fabrication comprenant de tels composes, ainsi que des procedes et des intermediaires utiles pour preparer les composes, et des procedes d'utilisation des composes et des compositions de ceux-ci.

This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.

Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.

L'invention concerne des composes de structures (1) et (2) modifiant l'activite de PPAR. L'invention concerne egalement des sels pharmaceutiquement acceptables de ces composes, des compositions pharmaceutiquement acceptables comprenant ces composes ou leurs sels, ainsi que des methodes d'utilisation desdits composes comme agents therapeutiques destines a traiter ou prevenir l'hyperlipidemie et l'hypercholesterolemie chez un mammifere. La presente invention se rapporte en outre a des procedes de fabrication des composes susmentionnes.

A series of 2-aryl-4H-3,1-benzoxazin-4-ones have been synthesized and tested for inhibitory activity against C1r serine protease. Compounds were found that were equipotent and more selective than the reference compound FUT-175.