ABSTRACT
Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.
Subject(s)
Drug Discovery , Orexin Receptor Antagonists/pharmacology , Orexin Receptors/metabolism , Pyrimidines/pharmacology , Quinazolines/pharmacology , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Orexin Receptor Antagonists/chemical synthesis , Orexin Receptor Antagonists/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Subject(s)
Drug Discovery , Orexin Receptor Antagonists , Pyridines/pharmacology , Sleep Initiation and Maintenance Disorders/drug therapy , Thiazoles/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
Subject(s)
Amides/pharmacology , Proline/analogs & derivatives , Proline/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Amides/chemical synthesis , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/pharmacology , Kinetics , Neuropeptides/chemistry , Neuropeptides/pharmacology , Orexin Receptors , Orexins , Proline/chemical synthesis , RatsABSTRACT
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.
