ABSTRACT
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.
Subject(s)
Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Blood-Brain Barrier/drug effects , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical/methods , Half-Life , Humans , Huntington Disease/drug therapy , Huntington Disease/metabolism , Inhibitory Concentration 50 , Madin Darby Canine Kidney Cells/drug effects , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 10/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Drug Discovery , Urea/chemistry , Urea/pharmacology , Anti-HIV Agents/chemistry , HIV-1/drug effectsABSTRACT
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.
Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Carboxylic Acids/pharmacokinetics , Amides/chemistry , Animals , Anti-HIV Agents/blood , Anti-HIV Agents/chemistry , Carboxylic Acids/blood , Carboxylic Acids/chemistry , Drug Discovery , RatsABSTRACT
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , CCR5 Receptor Antagonists , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HIV-1/drug effects , Piperidines/chemistry , Piperidines/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/metabolism , Area Under Curve , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/metabolism , Benzimidazoles , Dogs , Drug Design , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolism , Haplorhini , Humans , Piperidines/chemical synthesis , Piperidines/metabolism , Rats , Structure-Activity Relationship , Sulfonamides , TropanesABSTRACT
We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Putrescine/chemistry , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Cell Line , Disease Models, Animal , HIV Infections/drug therapy , HIV-1/drug effects , Inhibitory Concentration 50 , Rats , Rats, Sprague-DawleyABSTRACT
Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , HIV-1/drug effects , Urea/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line, Tumor , Dogs , Drug Evaluation, Preclinical , Haplorhini , Humans , Pyridines/chemistry , Rats , Receptors, CCR5/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacokinetics , Virus Replication/drug effectsABSTRACT
Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
Subject(s)
Amines/chemistry , Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , HIV-1/drug effects , Phenylurea Compounds/chemistry , Sulfonamides/chemistry , Urea/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line, Tumor , Drug Evaluation, Preclinical , Humans , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, CCR5/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Urea/chemical synthesis , Urea/pharmacokinetics , Virus Replication/drug effectsABSTRACT
Using AMD070 as a starting point for structural modification, a novel series of isoquinoline CXCR4 antagonists was developed. A structure-activity scan of alternate lower heterocycles led to the 3-isoquinolinyl moiety as an attractive replacement for benzimidazole. Side chain optimization in the isoquinoline series led to a number of compounds with low nanomolar anti-HIV activities and promising rat PK properties.
Subject(s)
Anti-HIV Agents/chemical synthesis , Isoquinolines/chemistry , Receptors, CXCR4/antagonists & inhibitors , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Benzimidazoles/chemistry , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Rats , Receptors, CXCR4/metabolism , Structure-Activity RelationshipABSTRACT
The lead optimization of a series of N-substituted benzimidazole CXCR4 antagonists is described. Side chain modifications and stereochemical optimization led to substantial improvements in potency and protein shift to afford compounds with low nanomolar anti-HIV activity.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , HIV Infections/drug therapy , HIV-1/drug effects , Receptors, CXCR4/antagonists & inhibitors , Cell Line , Humans , Inhibitory Concentration 50 , Receptors, CXCR4/metabolismABSTRACT
Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Infections/drug therapy , HIV-1/drug effects , Phenanthrolines/chemistry , Phenanthrolines/pharmacology , Receptors, CXCR4/antagonists & inhibitors , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line , Dogs , Humans , Models, Molecular , Phenanthrolines/chemical synthesis , Phenanthrolines/pharmacokinetics , Rats , Receptors, CXCR4/metabolismABSTRACT
GSK812397 is a potent entry inhibitor of X4-tropic strains of HIV-1, as demonstrated in multiple in vitro cellular assays (e.g., in peripheral blood mononuclear cells [PBMCs] and a viral human osteosarcoma [HOS] assay, mean 50% inhibitory concentrations [IC50s]+/-standard errors of the means were 4.60+/-1.23 nM and 1.50+/-0.21 nM, respectively). The primary in vitro potency of GSK812397 was not significantly altered by the addition of serum proteins (2.55 [+/-0.12]-fold shift in the presence of human serum albumin and alpha-acid glycoprotein in the PBMC assay). Pharmacological characterization of GSK812397 in cell-based functional assays revealed it to be a noncompetitive antagonist of the CXCR4 receptor, with GSK812397 producing a concentration-dependent decrease in both an SDF-1-mediated chemotaxis and intracellular calcium release (IC50s were 0.34+/-0.01 nM and 2.41+/-0.50 nM, respectively). With respect to the antiviral activity of GSK812397, it was effective against a broad range of X4- and X4R5-utilizing clinical isolates. The potency and efficacy of GSK812397 were dependent on the individual isolate, with complete inhibition of infection observed with 24 of 30 isolates. GSK812397 did not show any detectable in vitro cytotoxicity and was highly selective for CXCR4, as determined using a wide range of receptors, enzymes, and transporters. Moreover, GSK812397 demonstrated acceptable pharmacokinetic properties and bioavailability across species. The data demonstrate that GSK812397 has antiviral activity against a broad range of X4-utilizing strains of HIV-1 via a noncompetitive antagonism of the CXCR4 receptor.
Subject(s)
Aminoquinolines/pharmacology , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Imidazoles/pharmacology , Receptors, CXCR4/antagonists & inhibitors , Cell Line , Cell Line, Tumor , Cells, Cultured , Chemotaxis/drug effects , Enzyme Activation/drug effects , HIV Fusion Inhibitors/pharmacokinetics , HIV Infections/prevention & control , HIV-1/physiology , Humans , Virus Replication/drug effectsABSTRACT
Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.
Subject(s)
Antiviral Agents/therapeutic use , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Antiviral Agents/pharmacology , Cell Line, Tumor , HIV/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , Humans , Models, ChemicalABSTRACT
Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , HIV Infections/drug therapy , Piperidines/chemical synthesis , Animals , Anti-HIV Agents/pharmacology , CHO Cells , Chemistry, Pharmaceutical/methods , Cricetinae , Cricetulus , Drug Design , HIV-1/metabolism , Inhibitory Concentration 50 , Molecular Conformation , Piperidines/pharmacology , Protein Structure, Tertiary , Rats , Receptors, CCR5/chemistryABSTRACT
We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , HIV-1/drug effects , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, CCR5/chemistry , Receptors, CCR5/metabolism , Antiviral Agents/chemistry , Drug Evaluation, Preclinical , Ligands , Molecular Structure , Piperidines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.