ABSTRACT
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
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
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
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
Synthesis of several pyrazolo[1,5-c]pyrimidines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.
Subject(s)
Antiviral Agents/chemistry , Herpesviridae/drug effects , Pyrimidines/chemistry , Triazines/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Chlorocebus aethiops , Herpesviridae Infections/drug therapy , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Triazines/chemical synthesis , Triazines/pharmacokinetics , Vero CellsABSTRACT
Several novel amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines were synthesized which had potent activity against HIV-1. The synthetic approaches adopted allowed for variation of the substitution pattern and resulting changes in antiviral activity are highlighted. This led to the identification of compounds with low and sub-nanomolar anti-HIV-1 activity.
Subject(s)
Amines/chemistry , Anti-HIV Agents/chemistry , Benzimidazoles/chemistry , HIV-1/drug effects , Receptors, CXCR4/antagonists & inhibitors , Acquired Immunodeficiency Syndrome/drug therapy , Amines/chemical synthesis , Amines/pharmacology , Aminoquinolines , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Butylamines , Cell Line, Tumor , Heterocyclic Compounds, 1-Ring/chemistry , Humans , Receptors, CXCR4/metabolismABSTRACT
Synthesis of a series of tetrahydrocarbazole amides with potent activity against human papillomaviruses is described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole and the amide are outlined and resulting changes in antiviral activity and certain developability parameters are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the single digit nanomolar range were identified and N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide was selected for further evaluation.
Subject(s)
Amides/chemical synthesis , Carbazoles/chemical synthesis , Papillomaviridae/metabolism , Administration, Oral , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Carbazoles/pharmacology , Chlorocebus aethiops , Cytochrome P-450 Enzyme System/chemistry , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Vero CellsABSTRACT
The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.
Subject(s)
Antiviral Agents/chemistry , Carbazoles/chemistry , Papillomaviridae/drug effects , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Carbazoles/pharmacokinetics , Carbazoles/toxicity , Cell Line , DNA, Viral/drug effects , Female , Humans , Rats , Structure-Activity RelationshipABSTRACT
Synthesis of a series of 5-substituted as well as 5,7-disubstituted 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar to or better than acyclovir are described.
Subject(s)
Acyclovir/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Herpesviridae/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A recently disclosed series of pyrazolo[1,5-a]pyridine inhibitors of herpes virus replication has been closely examined herein for effects of the C3 substituent on antiviral activity. Significant changes in activity are observed by alterations of the heteroatom basicity and orientation of the group at C3. These results in combination with previous studies have served to further elaborate the minimal pharmacophore required for potency of this novel series of antiviral agents. During the course of these studies, several novel synthetic approaches were developed and are described.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Herpesviridae/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Herpesviridae/physiology , Humans , Pyridines/chemistry , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Synthesis of a series of 2-aryl-3-pyrimidyl-imidazo[1,2-a]pyridines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the 2-aryl, 3-heteroaryl as well as other imidazopyridine substituents are outlined and resulting effects on antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.
Subject(s)
Antiviral Agents/chemical synthesis , Herpesviridae/drug effects , Pyrimidines/chemical synthesis , Antiviral Agents/pharmacology , Imidazoles/chemistry , Microbial Sensitivity Tests , Pyridines/chemistry , Pyrimidines/pharmacologyABSTRACT
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Antiviral Agents/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Adenosine/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Antiviral Agents/pharmacology , Cell Line , HIV-1/drug effects , HIV-2/drug effects , Hepatitis B virus/drug effects , Humans , In Vitro Techniques , Intestinal Mucosa/metabolism , Liver/metabolism , Nucleotides/chemical synthesis , Nucleotides/pharmacology , Organophosphorus Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
This review highlights selected examples of peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 to advance novel anti-HIV pharmaceuticals that inhibit initial stages of the viral cycle; namely, attachment and entry. Some of these approaches have culminated in the development of peptide-based drugs, while other have exploited peptides as enabling tools toward the identification of small-molecule lead compounds. Both of these conceptually different approaches have facilitated lead optimization of molecules with complementary and often surprising anti-HIV pharmacological properties, supporting their role in pharmaceutical development. Furthermore, such molecules enabled mechanistic elucidation of viral attachment and entry and provided additional insights toward achieving the desired drug profile.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Design , HIV-1/drug effects , Peptide Fragments/pharmacology , Receptors, CCR5/metabolism , Receptors, CXCR4/metabolism , Virus Replication/drug effects , Amino Acid Sequence , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , CCR5 Receptor Antagonists , HIV Envelope Protein gp120/metabolism , HIV Envelope Protein gp41/metabolism , HIV-1/metabolism , Humans , Models, Biological , Molecular Sequence Data , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Receptors, CCR5/chemistry , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/chemistryABSTRACT
A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir.
Subject(s)
Herpesviridae/drug effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Cell Line , Chlorocebus aethiops , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Pyridines/chemical synthesis , Pyridines/toxicity , Structure-Activity RelationshipABSTRACT
Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Phenol/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Antiviral Agents/chemistry , Cell Line , Chlorocebus aethiops , Humans , Microbial Sensitivity Tests , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effectsABSTRACT
We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.
Subject(s)
Anti-HIV Agents/chemical synthesis , Dideoxynucleosides/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Administration, Oral , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Biological Availability , Cell Line , Cell Line, Tumor , Dideoxynucleosides/pharmacokinetics , Dideoxynucleosides/pharmacology , HIV-1/drug effects , HIV-2/drug effects , Humans , Macaca fascicularis , Mice , Organophosphorus Compounds/pharmacokinetics , Organophosphorus Compounds/pharmacology , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/virologyABSTRACT
A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage intermediates. Detailed examination of the amine substituents at the C2' position of the pyrimidine and C7 position of the core pyrazolopyridine is described. The antiviral data suggests that non-polar amines are preferred for optimal activity. Additionally, the 2' position has been shown to require an NH group to retain activity levels similar to that of the gold standard acyclovir.
Subject(s)
Amines/chemistry , Antiviral Agents/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chlorocebus aethiops , Herpesviridae/drug effects , Herpesvirus 1, Cercopithecine/drug effects , Microbial Sensitivity Tests , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Vero CellsABSTRACT
Synthesis of phosphoramidate protides of carbocyclic D- and L-2',3'-dideoxy-2',3'-didehydro-7-deazaadenosine by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleosides against both HIV and HBV.
Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Amides/chemical synthesis , Antiviral Agents/chemical synthesis , HIV/drug effects , Hepatitis B virus/drug effects , Phosphoric Acids/chemical synthesis , Tubercidin/chemistry , Adenosine/pharmacology , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Lymphocytes/cytology , Lymphocytes/drug effects , Lymphocytes/virology , Molecular Structure , Phosphoric Acids/chemistry , Phosphoric Acids/pharmacology , Tubercidin/analogs & derivativesABSTRACT
Syntheses of phosphoramidate protides of several 2',3'-dideoxy-3'-fluoroadenosine derivatives by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleoside against HIV and HBV. Especially marked was the improvement in potency of phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine against both HIV and HBV.
Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Deoxyadenosines/chemical synthesis , Deoxyadenosines/pharmacology , Dideoxyadenosine/analogs & derivatives , HIV/drug effects , Hepatitis B virus/drug effects , Phosphoric Acids/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Cell Line, Tumor , Deoxyadenosines/chemistry , Deoxyadenosines/toxicity , Dideoxyadenosine/chemical synthesis , Dideoxyadenosine/chemistry , Dideoxyadenosine/pharmacology , Dideoxyadenosine/toxicity , Humans , Inhibitory Concentration 50 , Lymphocytes/cytology , Lymphocytes/drug effects , Lymphocytes/virology , Molecular StructureABSTRACT
2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo[1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80-90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-d/l-erythrofuranosyl)imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix alpha gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the alpha-d anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most active member of the series, while the beta-anomers all proved to be inactive.