ABSTRACT
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Subject(s)
Amides/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/metabolism , Heterocyclic Compounds/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Amides/administration & dosage , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Humans , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Amides/pharmacology , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemistry , Tartrates/chemistry , ADAM17 Protein , Amides/chemical synthesis , Amides/chemistry , Animals , Biological Availability , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , RatsABSTRACT
The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM.
Subject(s)
Piperazines/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Receptors, CXCR3/agonists , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperazine , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , Arthritis, Rheumatoid/drug therapy , Protease Inhibitors/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Acetylene/analogs & derivatives , Acetylene/pharmacokinetics , Acetylene/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Dogs , Haplorhini , Humans , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic use , RatsABSTRACT
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , ADAM17 Protein , Animals , Rats , Structure-Activity RelationshipABSTRACT
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hydantoins/pharmacology , ADAM17 Protein , Enzyme Inhibitors/chemistry , Hydantoins/chemistry , Hydrogen Bonding , Models, Molecular , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Subject(s)
Receptor, Cannabinoid, CB2/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfones/chemistry , Sulfones/chemical synthesis , Animals , Calcium Channels/metabolism , Cytochrome P-450 Enzyme System , Drug Inverse Agonism , Humans , Piperidines/chemistry , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfones/pharmacokineticsABSTRACT
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
