Dihydropyridopyrazinones and dihydropteridinones as corticotropin-releasing factor-1 receptor antagonists: structure-activity relationships and computational modeling.

ABSTRACT

The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.