Efficacy and safety are the two key elements in the drug discovery and development processes. The primary goal for pharmaceutical research companies is to identify and manufacture therapeutic agents ...that are safe and efficacious for patients. In principle, benefits versus risks have to be considered for target patient populations. The risks are relatively high in life threatening diseases, e.g. cancer, compared to general areas, e.g. inflammation. Pharmacology, medicinal chemistry, pharmaceutical sciences, safety assessment, drug metabolism and pharmacokinetics (DMPK), clinical research, etc. are the essential multidisciplinary R&D functions assembled within the pharmaceutical R&D engine to accomplish the aforementioned mission. Pharmacokinetics (PK) is generally viewed as the universal biomarker which reflects the processes of how a drug molecule is absorbed (e.g. ka), distributed (e.g. Vd) in the body, and cleared from the body through metabolism and excretion. The area under the drug plasma concentration versus time curve (AUC) provides an indirect assessment of the exposure level and duration of action of the therapeutic agent at the site of action (e.g. synovial fluid, tumor, brain). An ideal drug candidate should possess a plasma drug level which is above the therapeutic concentration (i.e. efficacious) and below the toxic concentration (i.e. safe). In general, the therapeutic index is calculated by dividing the plasma exposure at the NO (toxic) Effect Level (NOEL), or NO Adverse Effect Level (NOAEL), by the minimum plasma concentration required for efficacy (e.g. EC50) and the safety margin is calculated by dividing NOEL (or NOAEL) plasma concentration by the maximum plasma drug concentration (Cmax) achieved at an efficacious dose.
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.
