Application of Prospective Models

For small molecules, most prospective (aka predictive ) models are used to identify potential chemical structure-mediated, off-target effects so that chemists can design away from unwanted features and chose the candidate with the overall best profile. The application of prospective models largely encompasses the evaluation of (i) selectivity/promis-cuity, (ii) secondary and safety pharmacology, (iii) intrinsic cytotoxicity, (iv) ADME-based drivers of toxicity, and (v) genotoxidty. This core profiling battery is based on drivers [Pg.17]

Prospective Lead Optimization Core Components Candidate Target Profile [Pg.18]

Selectivity High selectivity Low promiscuity No/acceptable functional effects (agonist/antagonist) [Pg.18]

ADME/PKrisk Low intrinsic clearance No/minimal reactive metabohte formation/covalent binding (burden) Acceptable distribution profile (tissue/cellular) [Pg.18]

Genetic toxicity (non-life-threatening indications) Eliminate mutagens and clastogens Minimize aneugens [Pg.18]

Big Chemical Encyclopedia