ABSTRACT
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.
Subject(s)
Dopamine D2 Receptor Antagonists , Receptors, Dopamine D1/agonists , Schizophrenia/drug therapy , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Animals , Drug Design , Male , Mice , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Schizophrenia/pathology , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesisABSTRACT
In this manuscript, the synthesis and SAR evaluation of a novel pyrazinone class of tryptase inhibitors is described. Chemical optimization of the P1 and P4 groups led to the identification of 7p (K(i)=93 nM) as a potent inhibitor of mast cell tryptase.
Subject(s)
Pyrazines/chemical synthesis , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Pyrazines/pharmacology , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , TryptasesABSTRACT
One common synthetic route creates small-molecule libraries directed toward two functionally distinct target families. The novel structural template 1 can independently display the necessary pharmacophore patterns for inhibition of members of two different biomolecular target families, the matrix metalloproteinases (MMPs) or the phosphodiesterases (PDEs). The incorporation of multiple target family directed design elements into combinatorial library design could help expedite the pharmaceutical lead discovery process. Z=OR' (PDE4), H (MMPs).
