ABSTRACT
The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D(2) partial agonists is described. Our goal was to optimize the affinities for the D(2), 5-HT(2A) and 5-HT(1A) receptors, such that the D(2)/5-HT(2A) ratio was greater than 5 to ensure maximal occupancy of these receptors when the D(2) occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED=0.3mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).
Subject(s)
Antipsychotic Agents/pharmacology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Receptors, Dopamine D2/agonists , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Bipolar Disorder/drug therapy , Drug Discovery , Haplorhini , Male , Molecular Structure , Naphthyridines/pharmacokinetics , Piperazine , Piperazines/pharmacokinetics , Rats , Receptors, Dopamine D2/chemistry , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
Subject(s)
Amides/chemical synthesis , Aza Compounds/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Neuroprotective Agents/chemical synthesis , Tacrolimus Binding Protein 1A/antagonists & inhibitors , Tacrolimus Binding Protein 1A/chemistry , Amides/chemistry , Aza Compounds/chemistry , Binding Sites , Heterocyclic Compounds, 4 or More Rings/chemistry , Hydrogen Bonding , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Ligands , Neuroprotective Agents/chemistry , Structure-Activity Relationship , Tacrolimus/chemistryABSTRACT
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.