ABSTRACT
1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC(50) values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Phenanthridines/chemical synthesis , Phenanthridines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Enzyme Inhibitors/chemistry , Phenanthridines/chemistry , Structure-Activity RelationshipABSTRACT
Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Nelfinavir/chemical synthesis , Nelfinavir/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/pharmacokinetics , Biological Availability , Callithrix , Dogs , Dose-Response Relationship, Drug , Female , HIV Protease Inhibitors/pharmacokinetics , HIV-1/drug effects , Macaca fascicularis , Male , Nelfinavir/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (Ki,app) approaching 0.10 microM. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.
Subject(s)
Carrier Proteins/antagonists & inhibitors , DNA-Binding Proteins/antagonists & inhibitors , Drug Design , Heat-Shock Proteins/antagonists & inhibitors , Urea/analysis , Amino Acid Isomerases/antagonists & inhibitors , Amino Acid Sequence , Carrier Proteins/chemistry , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , Heat-Shock Proteins/chemistry , Humans , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Peptidylprolyl Isomerase , Structure-Activity Relationship , Tacrolimus/chemistry , Tacrolimus Binding ProteinsABSTRACT
Calcineurin (CaN) is a calcium- and calmodulin-dependent protein serine/threonine phosphate which is critical for several important cellular processes, including T-cell activation. CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cytoplasmic binding proteins (cyclophilin and FKBP12, respectively). We report here the crystal structures of full-length human CaN at 2.1 A resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 A resolution. In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule. In the FKBP12-FK506-CaN complex, the auto-inhibitory element is displaced from the active site. The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcineurin, including a natural anchoring protein.
Subject(s)
Adaptor Proteins, Signal Transducing , Calmodulin-Binding Proteins/chemistry , Carrier Proteins/metabolism , DNA-Binding Proteins/metabolism , Heat-Shock Proteins/metabolism , Phosphoprotein Phosphatases/chemistry , Tacrolimus/metabolism , A Kinase Anchor Proteins , Amino Acid Sequence , Binding Sites , Calcineurin , Calcium/metabolism , Calmodulin-Binding Proteins/antagonists & inhibitors , Calmodulin-Binding Proteins/metabolism , Calmodulin-Binding Proteins/ultrastructure , Carrier Proteins/chemistry , Crystallization , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Heat-Shock Proteins/chemistry , Humans , Hydrogen Bonding , Models, Molecular , Molecular Sequence Data , Phosphoprotein Phosphatases/antagonists & inhibitors , Phosphoprotein Phosphatases/metabolism , Phosphoprotein Phosphatases/ultrastructure , Protein Conformation , Protein Structure, Secondary , Proteins/metabolism , Proteins/pharmacology , Recombinant Proteins/chemistry , Tacrolimus/chemistry , Tacrolimus Binding Proteins , Water/metabolismABSTRACT
A series of acyclic omega chain conjugated diene analogues of enisoprost were synthesized and evaluated for gastric antisecretory and diarrheagenic activities in comparison to enisoprost and a previously identified cyclic dienyl analogue. Several novel approaches to the cuprate reagents involved in the synthesis of the series are described. From this SAR study, it appears that both the conjugated diene and the overall space filling characteristics of the omega chain are important components to the pharmacological profiles and selectivity of these compounds and that a cyclic structure is not required.
