ABSTRACT
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.
Subject(s)
Benzamides/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Models, Molecular , Structure-Activity RelationshipABSTRACT
Crystallographic structural information was used in the design and synthesis of a number of bioisosteric derivatives to replace the amide moiety in a lead series of p38α inhibitors which showed general hydrolytic instability in human liver preparations. Triazole derivative 13 was found to have moderate bioavailability in the rat and demonstrated potent in-vivo activity in an acute model of inflammation.
Subject(s)
Amides/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Hydrogen Bonding , Indoles/chemistry , Indoles/pharmacokinetics , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Naphthyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Binding Sites , Cell Line , Crystallography, X-Ray , Humans , Inflammation/drug therapy , Inflammation/etiology , Lipopolysaccharides/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Monocytes/drug effects , Monocytes/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Protein Binding , Protein Conformation , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Optimisation of a series of indolin-2-one p38α inhibitors was achieved via both blocking of a potential metabolic 'hot spot' and by increasing overall polarity of the lead series leading to non-cytotoxic compounds which showed improved oral bioavailabilities in the rat.
Subject(s)
Indoles/pharmacology , Mitogen-Activated Protein Kinase 14/analysis , Animals , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Structure , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The use of structure-based design and molecular modeling led to the discovery of indolin-2-one derivatives as potent and selective p38α inhibitors. The predicted binding mode was confirmed by X-ray crystallography.
Subject(s)
Drug Design , Indoles/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , Structure-Activity RelationshipABSTRACT
A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Drug Design , Oxides/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/therapeutic use , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/drug therapy , Catalytic Domain , Cell Line , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , Substrate Specificity , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/blood , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
Subject(s)
Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/drug effects , Prodrugs/pharmacology , Sulfones/pharmacology , Sulfoxides/pharmacology , Animals , Crystallography, X-Ray , Cyclooxygenase 1/drug effects , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Drug Evaluation, Preclinical , Humans , Male , Models, Molecular , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfoxides/chemical synthesis , Sulfoxides/chemistryABSTRACT
The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.
Subject(s)
Cyclooxygenase 2 Inhibitors/pharmacology , Lactones/chemistry , Lactones/pharmacology , Prodrugs/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Safrole/analogs & derivatives , Sulfones/chemistry , Sulfones/pharmacology , Animals , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/blood , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Etoricoxib , Humans , Isomerism , Lactones/blood , Lactones/chemical synthesis , Male , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Pyridines/blood , Pyridines/chemical synthesis , Rats , Rats, Wistar , Safrole/chemistry , Solubility , Sulfones/blood , Sulfones/chemical synthesis , Temperature , ThermodynamicsABSTRACT
A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
