Biochemical Mechanisms of New Molecular Entities (NMEs) approved by United States FDA during 2001‐2004: Mechanisms leading to optimal efficacy and safety.

The United States FDA approved 85 New Molecular Entities (NMEs) during the period from January 2001 to November 2004 of which 61 were pharmaceuticals with known molecular targets. The majority targeted enzymes (48%) or G‐protein coupled receptors (GPCRs) (33%). Eighty three percent of the NMEs interacted at the same site as endogenous effector; either as competitive inhibitor/antagonist (70%) or agonist (13%). Three biochemical operations defined the modes of action of the NMEs: 1) mass action competition (passive), 2) a drug stabilized conformational change in the target that is important to the response (conformational) and/or 3) the life‐time of the drug‐target complex is of sufficient duration that the response is susceptible to an alternative, kinetically faster reaction (non‐equilibrium kinetic). Approximately 80% of the NMEs elicit a response utilizing conformational and/or non‐equilibrium kinetic mechanisms. The remaining 20% of NMEs passively compete with the endogenous substrate or ligand to block the endogenous effectors response. These observations indicate that equilibrium binding alone may not be sufficient for maximal therapeutic utility. A key determinant of the biochemical mode of action for these NMEs is to minimize the potential for toxicity, either by providing a maximal response at a low dose to minimize off‐target toxicities, or by providing a mechanism to minimize the incidence of mechanism‐based toxicity while retaining a sufficiently efficacious response. This principle appears to be independent of target class and provides insight as to intrinsic biochemical features and approaches required for a maximal therapeutic index.