Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss
In this Drug Annotation, the discovery of an antagonist of the melanocortin-4 receptor (MC4R) and clinical candidate: PF-07258669 is described. MC4R signalling is responsible for the regulation of food intake via the suppression of appetite. Inhibition of this target is thus expected to provide a potential treatment or reversal of appetite loss linked to a number of chronic illnesses.
The discovery began by screening a ~28,000-strong compound library belonging to Pfizer that was formed based on affinity data from previous MC4R work (J. Med. Chem. 2010, 53, 8, 3183–3197), the library was screened using a functional MC4R inverse agonist assay. After observing time-dependent increases in potency for certain batches of a hit compound, it was revealed that a moderately potent compound was rearranging upon storage to an inverse agonist of MC4R with a single digit nanomolar potency, providing a novel scaffold that was progressed into lead optimisation.
Navigation of liabilities, such as hERG inhibition and time-dependent inhibition of CYP450, was achieved by core swapping – after which, potency was re-optimised by some excellent 3D rational design work. This work involved the analysis of data from: publicly accessible crystal structures, solution-phase NMR spectroscopy and free energy calculations, culminating in the discovery of the conformationally-restricted spirocycle PF-07258669 that displayed a dose-dependent food intake and body weight increase in an aged rat anorexia model. The candidate is currently undergoing phase I clinical trials.
Michelle R. Garnsey*, Jana Polivkova* et. al.