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2.
Open Med Chem J ; 9: 13-26, 2015.
Article in English | MEDLINE | ID: mdl-25937848

ABSTRACT

A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

3.
J Med Chem ; 57(5): 1673-93, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24446688

ABSTRACT

Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Japan, Canada, and USA.


Subject(s)
Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 3-Ring/chemistry , Sulfonamides/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Simeprevir , Sulfonamides/pharmacology
4.
J Med Chem ; 57(5): 1836-44, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24345201

ABSTRACT

The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 µM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 µM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Prodrugs/pharmacology , Ribonucleosides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Area Under Curve , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Humans , Magnetic Resonance Spectroscopy , Rats , Rats, Sprague-Dawley , Ribonucleosides/chemistry , Ribonucleosides/pharmacokinetics
5.
J Med Chem ; 56(22): 8999-9007, 2013 Nov 27.
Article in English | MEDLINE | ID: mdl-24160253

ABSTRACT

To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 µM, respectively.


Subject(s)
Alcohols/chemistry , Drug Design , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Chemistry Techniques, Synthetic , Crystallography, X-Ray , HIV Protease/chemistry , HIV Protease Inhibitors/chemistry , Macrocyclic Compounds/chemistry , Models, Molecular , Protein Conformation
6.
Bioorg Med Chem Lett ; 23(1): 310-7, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23177258

ABSTRACT

The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R(3)) at the para-position of the P1' benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R(1)) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC(50)s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS.


Subject(s)
Carbamates/chemical synthesis , Dipeptides/chemical synthesis , Drug Design , HIV Protease Inhibitors/chemical synthesis , HIV Protease/chemistry , HIV-1/enzymology , Pyridines/chemical synthesis , Alkylation , Animals , Carbamates/chemistry , Carbamates/pharmacokinetics , Dipeptides/chemistry , Dipeptides/pharmacokinetics , HIV Protease/metabolism , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , Half-Life , Halogenation , Humans , Microsomes, Liver/metabolism , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem ; 20(14): 4377-89, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22698785

ABSTRACT

A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Ethylamines/chemistry , Amyloid Precursor Protein Secretases/metabolism , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Ethylamines/chemical synthesis , Protein Structure, Tertiary , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 22(9): 3265-8, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22472694

ABSTRACT

4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 µM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.


Subject(s)
Antiviral Agents/chemistry , Cytidine/analogs & derivatives , Deoxycytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/pharmacology , Animals , Antiviral Agents/pharmacology , Cytidine/pharmacology , Deoxycytidine/pharmacology , Drug Discovery , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Rats , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects
9.
J Med Chem ; 55(6): 2724-36, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-22376008

ABSTRACT

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure ß-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 µM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 µM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , Lactams/chemistry , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , HIV Protease/metabolism , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Humans , Lactams/chemical synthesis , Lactams/pharmacology , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
10.
Antimicrob Agents Chemother ; 55(8): 3812-20, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21576430

ABSTRACT

Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2'-deoxy-2'-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.


Subject(s)
Antiviral Agents/pharmacology , Cytidine/analogs & derivatives , Hepacivirus/drug effects , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Cell Line , Cytidine/metabolism , Cytidine/pharmacology , Deoxycytidine Kinase/metabolism , Humans , Mitochondria/drug effects , Phenotype , Phosphorylation , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , RNA, Viral/genetics , RNA, Viral/metabolism , Spiro Compounds/metabolism , Viral Nonstructural Proteins/genetics
11.
Bioorg Med Chem ; 19(1): 145-55, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21183353

ABSTRACT

Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and ß-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19µM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Phenylbutyrates/pharmacology , Protease Inhibitors/pharmacology , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Mass Spectrometry , Phenylbutyrates/chemistry , Protease Inhibitors/chemistry
12.
Bioorg Med Chem Lett ; 21(1): 358-62, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21112780

ABSTRACT

Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the K(i) and the human plasma renin activity (HPRA)IC(50) was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (K(i) = 3.3 nM and HPRA IC(50) = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (K(i) = 34 nM and HPRA IC(50) = 56 nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin.


Subject(s)
Macrocyclic Compounds/chemistry , Protease Inhibitors/chemical synthesis , Renin/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Cathepsin D/antagonists & inhibitors , Cathepsin D/metabolism , Crystallography, X-Ray , Drug Design , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Renin/metabolism
13.
J Med Chem ; 53(22): 8150-60, 2010 Nov 25.
Article in English | MEDLINE | ID: mdl-21033671

ABSTRACT

The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 µM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 µM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.


Subject(s)
Antiviral Agents/chemical synthesis , Cytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cell Line , Cytidine/chemical synthesis , Cytidine/chemistry , Cytidine/pharmacology , Dogs , Esters , Humans , Male , Models, Molecular , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Virus Replication
14.
Bioorg Med Chem Lett ; 20(14): 4004-11, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20541405

ABSTRACT

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Area Under Curve , Caco-2 Cells , Humans , Intracellular Signaling Peptides and Proteins , Microsomes, Liver/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Structure-Activity Relationship
15.
J Med Chem ; 53(4): 1458-64, 2010 Feb 25.
Article in English | MEDLINE | ID: mdl-20128595

ABSTRACT

Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 K(i) << 1 nM and displays >1000-fold selectivity over cathepsin D.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylenes/chemical synthesis , Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Cathepsin D/antagonists & inhibitors , Crystallography, X-Ray , Drug Design , Ethylenes/chemistry , Ethylenes/pharmacology , Humans , Hydrogen Bonding , Models, Molecular , Stereoisomerism , Structure-Activity Relationship
16.
Bioorg Med Chem ; 18(4): 1711-23, 2010 Feb 15.
Article in English | MEDLINE | ID: mdl-20122837

ABSTRACT

In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Ethylenes/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet , Structure-Activity Relationship
18.
Bone ; 46(5): 1400-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20097319

ABSTRACT

In mice and humans, the effect of genetic deficiency of cathepsin K (catK) is impaired bone resorption, or osteopetrosis. Inhibition of catK is therefore a promising strategy for the treatment of osteoporosis. The enzyme acts in an acid environment. This provides a further potential opportunity: if the inhibitor is basic it is more likely to accumulate in membrane-bound acidic compartments (lysosomotropism), so minimizing off-target effects. However, the resorptive hemivacuole is not membrane-bound, and so might not retain lysosomotropic compounds. We therefore elected to determine whether the osteoclastic resorptive apparatus supports such accumulation. First, we attempted to compare the persistence of a lysosomotropic dye in the hemivacuole versus intracellular vesicles. To our surprise the dye could not be detected in the ruffled border region by confocal microscopy. We found that this could be explained by the tight packing of the folds of the ruffled border, and their close apposition to the bone surface. We also found that the dye persisted similarly in resorbing osteoclasts and macrophages, consistent with the notion that resorbing osteoclasts support lysosomotropism. Next, we compared the ability of basic and non-basic inhibitors of catK to suppress bone resorption by human osteoclasts. We found that basic compounds were considerably more potent than non-basic compounds at suppression of osteoclastic resorption than would be anticipated from their potency as enzyme inhibitors. Also consistent with osteoclastic lysosomotropism, basic inhibitors suppressed resorption for substantially longer than a non-basic inhibitor after washout from cell cultures. Furthermore, selectivity of basic inhibitors for inhibition of catK versus other cathepsins persisted: concentrations that inhibited catK in osteoclasts had no detectable effect on cathepsin S (catS) in a cell-based assay. This data is consistent with accumulation and enrichment of such basic inhibitors in the resorptive apparatus of the osteoclast, allowing for prolonged efficacy at the intended site of action. Our results suggest a major advantage for lysosomotropic compounds as inhibitors of bone resorption by osteoclasts in osteoporosis and other diseases caused by excessive osteoclastic activity.


Subject(s)
Bone Resorption/metabolism , Cathepsin K/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Osteoclasts/metabolism , Animals , Biphenyl Compounds/pharmacology , Cells, Cultured , Female , Humans , Macrophages/drug effects , Macrophages/metabolism , Macrophages/ultrastructure , Male , Mice , Microscopy, Confocal , Microscopy, Electron, Transmission , Osteoclasts/drug effects , Osteoclasts/ultrastructure
19.
J Med Chem ; 53(2): 607-15, 2010 Jan 28.
Article in English | MEDLINE | ID: mdl-19961222

ABSTRACT

By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.


Subject(s)
Alcohols/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Alcohols/pharmacology , Antiviral Agents/pharmacology , Crystallography, X-Ray , HIV Protease/genetics , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/genetics , Inhibitory Concentration 50 , Molecular Mimicry , Mutation, Missense
20.
Eur J Med Chem ; 45(1): 160-70, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19926360

ABSTRACT

The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 microM and 0.33 microM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.


Subject(s)
Alcohols/chemistry , Alcohols/pharmacology , Drug Design , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , Alcohols/chemical synthesis , Alcohols/metabolism , Animals , Cell Line , Drug Resistance, Viral , HIV Protease/chemistry , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/metabolism , Models, Molecular , Permeability , Protein Conformation , Structure-Activity Relationship
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