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1.
J Med Chem ; 57(5): 1902-13, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-23672667

ABSTRACT

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.


Subject(s)
Antiviral Agents/pharmacology , Boronic Acids/chemistry , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Drug Resistance, Viral/genetics , Hepacivirus/enzymology , Hepacivirus/genetics , Magnetic Resonance Spectroscopy , Models, Molecular , Structure-Activity Relationship , Viral Nonstructural Proteins/antagonists & inhibitors
2.
Bioorg Med Chem Lett ; 22(24): 7351-6, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23142614

ABSTRACT

We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Animals , Antiviral Agents/chemistry , Carbamates/chemistry , Dose-Response Relationship, Drug , Drug Resistance, Viral/genetics , Guanidines/chemistry , Hepacivirus/enzymology , Hepacivirus/genetics , Microbial Sensitivity Tests , Molecular Structure , Oxamic Acid/chemistry , Rats , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Urea/chemistry , Viral Nonstructural Proteins/metabolism
3.
J Med Chem ; 55(7): 3021-6, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-22471376

ABSTRACT

The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.


Subject(s)
Antiviral Agents/chemical synthesis , Drug Resistance, Viral , Hepacivirus/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Hepacivirus/enzymology , Hepacivirus/genetics , Hydrophobic and Hydrophilic Interactions , Liver/metabolism , Mutation , Rats , Replicon/drug effects , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/pharmacology , Viral Nonstructural Proteins/genetics
4.
Bioorg Med Chem Lett ; 22(8): 2993-6, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22425454

ABSTRACT

A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.


Subject(s)
Drug Discovery , Hepacivirus/drug effects , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Cyclopropanes , Hepacivirus/genetics , Humans , Hydroxylation , Inhibitory Concentration 50 , Isoindoles , Lactams/chemistry , Lactams/pharmacology , Lactams, Macrocyclic , Molecular Structure , Mutation , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology
5.
Bioorg Med Chem Lett ; 21(7): 2048-54, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21353550

ABSTRACT

We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.


Subject(s)
Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 20(24): 7493-7, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21041080

ABSTRACT

HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.


Subject(s)
Boron Compounds/chemistry , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Animals , Boron Compounds/chemical synthesis , Boron Compounds/pharmacokinetics , Catalytic Domain , Hepacivirus/drug effects , Male , Models, Molecular , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Virus Replication/drug effects
7.
Bioorg Med Chem Lett ; 20(24): 7317-22, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21067923

ABSTRACT

We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.


Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Isoquinolines/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Viral Nonstructural Proteins/metabolism
8.
Bioorg Med Chem Lett ; 20(19): 5695-700, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20801653

ABSTRACT

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.


Subject(s)
Boron Compounds/chemistry , Boronic Acids/chemistry , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Boron Compounds/chemical synthesis , Boron Compounds/pharmacology , Catalytic Domain , Crystallography, X-Ray , Hepacivirus/drug effects , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
9.
Bioorg Med Chem Lett ; 20(12): 3550-6, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20493689

ABSTRACT

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.


Subject(s)
Boronic Acids/chemical synthesis , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Boronic Acids/pharmacology , Boronic Acids/therapeutic use , Catalytic Domain , Drug Design , Hepacivirus/enzymology , Molecular Structure , Serine/chemistry , Structure-Activity Relationship
10.
ACS Med Chem Lett ; 1(8): 439-42, 2010 Nov 11.
Article in English | MEDLINE | ID: mdl-24900229

ABSTRACT

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.

11.
J Med Chem ; 51(21): 6631-4, 2008 Nov 13.
Article in English | MEDLINE | ID: mdl-18842034

ABSTRACT

Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.


Subject(s)
Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/enzymology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , rho-Associated Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Administration, Oral , Aldehydes/chemistry , Animals , Crystallography, X-Ray , Indazoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Rats , Structure-Activity Relationship , rho-Associated Kinases/metabolism
12.
J Med Chem ; 50(1): 2-5, 2007 Jan 11.
Article in English | MEDLINE | ID: mdl-17201404

ABSTRACT

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.


Subject(s)
Antihypertensive Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiology , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Blood Pressure/drug effects , In Vitro Techniques , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , rho-Associated Kinases
13.
J Med Chem ; 50(1): 6-9, 2007 Jan 11.
Article in English | MEDLINE | ID: mdl-17201405

ABSTRACT

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.


Subject(s)
Amides/chemical synthesis , Antihypertensive Agents/chemical synthesis , Indazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridones/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiology , Blood Pressure/drug effects , In Vitro Techniques , Indazoles/pharmacokinetics , Indazoles/pharmacology , Intracellular Signaling Peptides and Proteins/chemistry , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Protein Serine-Threonine Kinases/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , rho-Associated Kinases
14.
J Pharmacol Exp Ther ; 320(1): 89-98, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17018693

ABSTRACT

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxadiazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Vasodilator Agents/pharmacology , Animals , Antihypertensive Agents/pharmacology , Cells, Cultured , Cytokines/biosynthesis , Humans , Macrophages/drug effects , Macrophages/immunology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , rho-Associated Kinases
16.
Bioorg Med Chem Lett ; 16(19): 5226-30, 2006 Oct 01.
Article in English | MEDLINE | ID: mdl-16904316

ABSTRACT

We have developed efficient synthesis of morpholinone-based cyclic mimetics of the P1/P2 portion of the HIV-1 protease inhibitor Amprenavir. This effort led to discovery of allyl- and spiro-cyclopropyl-P2-substituted inhibitors 17 and 31, both 500 times more potent than the parent inhibitor 1. These results support morpholinones as novel mimetics of the P1/P2 portion of Amprenavir and potentially of other HIV-protease inhibitors, and thus provide a novel medicinal chemistry template for optimization toward more potent and drug-like inhibitors.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , Morpholines/chemical synthesis , Carbamates , Furans , HIV Protease Inhibitors/pharmacology , Humans , Molecular Mimicry , Morpholines/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Structure-Activity Relationship , Sulfonamides
17.
Protein Pept Lett ; 13(4): 369-76, 2006.
Article in English | MEDLINE | ID: mdl-16712513

ABSTRACT

Rho Kinase I (ROCK I) is a serine/threonine kinase that is involved in diverse cellular signaling. To further understand the physiological role of ROCK I and to identify and develop potent and selective inhibitors of ROCK I, we have overexpressed and purified a constitutively active dimeric human ROCK I (3-543) kinase domain using the Sf9-baculovirus expression system. In addition, using a limited proteolysis technique, we have identified a minimal functional subdomain of ROCK I that can be used in crystallization studies. The availability of multimilligram amounts of purified and well characterized functional human ROCK I kinase domains will be useful in screening and structural studies.


Subject(s)
Protein Serine-Threonine Kinases/biosynthesis , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Amides/pharmacology , Amino Acid Sequence , Animals , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Molecular Sequence Data , Molecular Weight , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/isolation & purification , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , Spodoptera , Staurosporine/pharmacology , rho-Associated Kinases
19.
Bioorg Med Chem Lett ; 16(4): 978-83, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16290936

ABSTRACT

Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.


Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Semicarbazones/pharmacology , Animals , Cathepsin K , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrogen-Ion Concentration , Hydrolysis , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Solubility , Structure-Activity Relationship
20.
Child Welfare ; 85(6): 899-918, 2006.
Article in English | MEDLINE | ID: mdl-17305041

ABSTRACT

Permanency planning for infants with prenatal substance exposure is challenging due to characteristics of the infants and the ongoing substance use or relapse of the parents. Visitation is a primary mechanism through which child welfare workers determine and support permanency planning. Productive use of visitation for permanency planning for infants with prenatal substance exposure is described, along with strategies for skillfully focusing visits on issues and needs relevant to this population.


Subject(s)
Child of Impaired Parents , Foster Home Care , Neonatal Abstinence Syndrome , Social Work/methods , Substance-Related Disorders/psychology , Decision Making , Humans , Infant , Infant, Newborn , Parent-Child Relations , Parenting , United States
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