ABSTRACT
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Azetidines/chemistry , Blood-Brain Barrier/metabolism , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Pyrimidinones/chemistry , 3',5'-Cyclic-AMP Phosphodiesterases/chemistry , Administration, Oral , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Crystallography, X-Ray , Cyclic GMP/cerebrospinal fluid , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Cyclopentanes/pharmacokinetics , Databases, Factual , Dogs , Drug Design , Humans , Models, Molecular , Molecular Structure , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable to large-scale preparation in a pilot plant environment. The key step is the aldol addition of nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule were each set independently by resolution of enantiomers. Intermediates along the synthetic routes were chosen to maximize opportunities for isolation and purification by crystallization.
