ABSTRACT
7-Heterocyclyl-5-aryl-pyrrolo[2,3-d]pyrimidines represent a new class of highly potent and selective inhibitors of the tyrosine kinase pp60(c-Src).
Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , src-Family Kinases/metabolismABSTRACT
7-Substituted-5-aryl-pyrrolo[2,3-d]pyrimidines have been prepared starting from alpha-bromoacetophenones. These compounds represent a novel class of potent inhibitors of the tyrosine kinase pp60(c-Src) with good specificity towards other tyrosine kinases (EGF-R, v-Abl).
Subject(s)
Alkanes/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Alkanes/chemistry , Alkanes/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Oncogene Proteins v-abl/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , src-Family Kinases/metabolismABSTRACT
5,7-Diphenyl-pyrrolo[2,3d]pyrimidines represent a new class of highly potent inhibitors of the tyrosine kinase c-Src (IC50 < 50 nM) with specificity against a panel of different tyrosine kinases. The substitution pattern on the two phenyl rings determines potency and specificity and provides a means to modulate cellular activity.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Animals , Blotting, Western , CSK Tyrosine-Protein Kinase , Chickens , Enzyme Inhibitors/pharmacology , Models, Molecular , Phosphorylation , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity Relationship , Substrate Specificity , src-Family KinasesABSTRACT
Bisphosphonates are used clinically to inhibit bone resorption but they may also cause renal damage. For the profiling of new potent bisphosphonates, their adverse renal effects were investigated in 2 rat models. In the first model, bisphosphonate was repeatedly injected (1 mg/kg, subcutaneously) over 2 weeks and the urinary excretion of malate dehydrogenase was monitored to assess nephrotoxic potential. Of the 6 new compounds tested, 3 markedly elevated malate dehydrogenase whereas 3 others caused only minor changes similar to those observed with 6 reference bisphosphonates that are already used clinically. On the basis of a therapeutic index (inhibition of bone resorption versus renal effects) 7-180 fold greater than that of other analogues, the compound CGP 42446 was further profiled. In the second model, CGP 42446 or pamidronate was infused (1.5-50 mg/kg, intravenously) into anaesthetized rats and the serum urea concentration was monitored as an indicator of renal dysfunction. Both compounds elevated serum urea in a time- and dose-dependent manner, but the ED100 value for CGP 42446 was 3.8-fold higher than that of pamidronate. It is concluded that CGP 42446 (zoledronate) has a low nephrotoxic potential and can be further developed as a new potent inhibitor of bone resorption.
Subject(s)
Diphosphonates/toxicity , Kidney Diseases/chemically induced , Animals , Bone Resorption/drug therapy , Diphosphonates/pharmacology , Disease Models, Animal , Injections, Subcutaneous , Kidney/drug effects , Kidney/physiology , Male , Parathyroid Glands/physiology , Parathyroid Glands/surgery , Rats , Rats, Inbred Strains , Thyroid Gland/physiology , Thyroid Gland/surgery , ThyroidectomyABSTRACT
OBJECTIVE: CGP 47969A is a novel and potent inhibitor of cytokine biosynthesis in human and murine monocytic cells. The effect of CGP 47969A on collagen induced arthritis (CIA) in DBA/1 mice was investigated and compared to that of prednisolone. METHODS: CIA was induced by intradermal injection of type II collagen in CFA at Day 0. CGP 47969A was applied orally, 5 times/week, starting at Day 15 after immunization. Arthritic signs were recorded 3 times/week for clinical scoring and radiographic analysis was performed at the end of the experiment at Day 60. Serum amyloid P (SAP) and anticollagen antibody titers were determined by ELISA at Day 60. RESULTS: CGP 47969A dose dependently reduced the incidence of arthritis from 93% in the positive control group to 60, 40, 30 and 10% at doses of 1, 5, 25 and 60 mg/kg/day, respectively. At a dose of 120 mg/kg, CGP 47969A totally prevented the occurrence of arthritis (ED50 between 1 and 5 mg/kg). Prednisolone at 3 and 30 mg/kg reduced the arthritis incidence to 70 and 30%, respectively. CGP 47969A dose dependently inhibited the joint destruction, as measured by radiographic scoring and its potency was comparable to that of prednisolone. The elevated serum levels of the positive acute phase protein SAP in arthritic animals were completely normalized by CGP 47969A at a dose of 60 mg/kg, however, neither CGP 47969A nor prednisolone influenced the plasma levels of anticollagen antibodies (IgG). CONCLUSION: Our results demonstrate that CGP 47969A is highly effective in CIA with a potency comparable to that of prednisolone. These promising results justify the expectation that this novel antiarthritic compound now under development might also be effective in the treatment of rheumatoid arthritis in man.
