ABSTRACT
We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.
Subject(s)
CCR5 Receptor Antagonists , Drug Discovery , Piperazines/pharmacology , Piperazines/pharmacokinetics , Pyrans/pharmacology , Pyrans/pharmacokinetics , Receptors, CCR2/antagonists & inhibitors , Biological Availability , Caco-2 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Pyrans/chemical synthesis , Pyrans/chemistryABSTRACT
This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.
Subject(s)
Drug Design , Receptors, CCR2/antagonists & inhibitors , Binding Sites , Models, Molecular , Structure-Activity RelationshipABSTRACT
We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.
ABSTRACT
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
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.
