ABSTRACT
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Crystallography, X-Ray , Drug Design , Melanoma, Experimental/drug therapy , Melanoma, Experimental/enzymology , Melanoma, Experimental/pathology , Mice , Mice, Nude , Models, Molecular , Mutation , Proto-Oncogene Proteins B-raf/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.
Subject(s)
Guanidine/chemistry , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Sulfhydryl Compounds/chemistry , Animals , Binding Sites , Brain/metabolism , Guanidine/analogs & derivatives , Guanidine/pharmacology , Inhibitory Concentration 50 , Mice , Plasma/metabolism , Structure-Activity Relationship , Sulfhydryl Compounds/pharmacology , Time FactorsABSTRACT
The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.
