The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
PDE10A is an important regulator of striatal signaling
that, when
inhibited, can normalize dysfunctional activity. Given the involvement
of dysfunctional striatal activity with schizophrenia, PDE10A inhibition
represents a potentially novel means for its treatment. With the goal
of developing PDE10A inhibitors, early optimization of a fragment
hit through rational design led to a series of potent pyrimidine PDE10A
inhibitors that required further improvements in physicochemical properties,
off-target activities, and pharmacokinetics. Herein we describe the
discovery of an isomeric pyrimidine series that addresses the liabilities
seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development
for the treatment of schizophrenia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.