Kent W. Neuenschwander

Structure-based design, synthesis, and profiling of potent and selective neuronal nitric oxide synthase (nNOS) inhibitors with an amidinothiophene hydroxypiperidine scaffold

A novel series of nNOS inhibitors with an amidinothiophene-hydroxypiperidine scaffold was designed based on X-ray structures and in-silico models. Three classes of inhibitors with this scaffold were synthesized and tested for their nNOS activity and eNOS selectivity. Compounds with a linear aliphatic amine linker demonstrated a superior property over those with a sulfonamide or an amide-like linker.

Design and synthesis of D1 agonist/D2 antagonist for treatment of schizophrenia

A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D(1)R occupancy (10 mg/kg, sc) and 75% of D(2)R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.