ABSTRACT
Human ß-nerve growth factor (ß-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit ß-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.
ABSTRACT
We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of an alternate projection into the solvent region to identify compounds with excellent potency, selectivity and pharmacokinetic profiles.
Subject(s)
Phosphodiesterase 5 Inhibitors/pharmacology , Pyrazines/pharmacology , Crystallography, X-Ray , Inhibitory Concentration 50 , Models, Molecular , Phosphodiesterase 5 Inhibitors/chemistry , Phosphodiesterase 5 Inhibitors/pharmacokinetics , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Solvents/chemistryABSTRACT
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
Subject(s)
Brain/metabolism , Phosphodiesterase 5 Inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Oral , Animals , Biological Availability , Blood Pressure/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Dose-Response Relationship, Drug , Drug Design , Humans , Male , Models, Chemical , Molecular Structure , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrazines/pharmacokinetics , Pyridines/pharmacokinetics , Rats , Rats, Inbred SHR , Rats, Sprague-DawleyABSTRACT
We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
Subject(s)
Phosphodiesterase 5 Inhibitors , Phosphodiesterase Inhibitors/chemistry , Pyrazines/chemistry , Pyridines/chemistry , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism , Dogs , Drug Discovery , Humans , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacokinetics , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 5/chemistry , Phosphodiesterase 5 Inhibitors , Pyrazines/chemical synthesis , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Catalytic Domain , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 6/chemistry , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Protein Structure, Tertiary , Pyrazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
