ABSTRACT
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Crohn Disease/drug therapy , Disease Models, Animal , Half-Life , Humans , Integrin alpha4beta1/metabolism , Integrins/metabolism , Jurkat Cells , Microsomes, Liver/metabolism , RatsABSTRACT
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Subject(s)
Integrin alpha4/chemistry , Polyethylene Glycols/chemistry , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Esters , Half-Life , Humans , Injections, Subcutaneous , Integrin alpha4/immunology , Integrin alpha4/metabolism , Jurkat Cells , RatsABSTRACT
The 4-isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Dicarbethoxydihydrocollidine/analogs & derivatives , Dihydropyridines/metabolism , Isoxazoles/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Caco-2 Cells , Calcium Channels/chemistry , Calcium Channels/metabolism , Dicarbethoxydihydrocollidine/chemical synthesis , Dicarbethoxydihydrocollidine/chemistry , Dicarbethoxydihydrocollidine/metabolism , Dihydropyridines/chemistry , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Magnetic Resonance Spectroscopy , Models, Chemical , Protein Binding , Structure-Activity Relationship , ThermodynamicsABSTRACT
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-ß in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Subject(s)
Aminopyridines/chemistry , Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Mitogen-Activated Protein Kinase 9/antagonists & inhibitors , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/chemistry , Protein Kinase Inhibitors/chemistry , Triazines/chemistry , Aminopyridines/pharmacokinetics , Aminopyridines/therapeutic use , Animals , Binding Sites , Central Nervous System/metabolism , Computer Simulation , Humans , Mice , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 10/metabolism , Mitogen-Activated Protein Kinase 9/metabolism , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/therapeutic useABSTRACT
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
