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1.
Future Med Chem ; 5(6): 641-52, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23617428

ABSTRACT

BACKGROUND: The ability of boron-containing compounds to undergo a number of novel binding interactions with drug target functional groups has recently been described. In an extension of this work, we have incorporated a boron-containing scaffold, the benzoxaborole, into several glycopeptides antibiotics. The aim of this work is to exploit the inherent reactivity of boron to gain additional interactions with the bacterial cell wall components to improve binding affinity and to thereby overcome resistance. RESULTS: Three antibacterial glycopeptides (vancomycin, eremomycin and teicoplanin aglycone) have been selected for the construction of a series of 12 new benzoxaborole-glycopeptide conjugates. The hybrid antibiotics, in which the benzoxaborole and glycopeptide moieties were separated by a linker, exhibited excellent antibacterial activity against Gram-positive bacteria, including those with intermediate susceptibility to glycopeptides. Some analogs also demonstrated activity against vancomycin-resistant enterococci. CONCLUSION: Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Boron Compounds/chemistry , Glycopeptides/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , Gram-Positive Bacteria/drug effects , Teicoplanin/analogs & derivatives , Teicoplanin/chemical synthesis , Teicoplanin/chemistry , Teicoplanin/pharmacology , Vancomycin/chemical synthesis , Vancomycin/chemistry , Vancomycin/pharmacology
2.
J Med Chem ; 44(24): 4137-56, 2001 Nov 22.
Article in English | MEDLINE | ID: mdl-11708916

ABSTRACT

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carbamates/chemical synthesis , Erythromycin/analogs & derivatives , Erythromycin/chemical synthesis , Ketolides , Protein Synthesis Inhibitors/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Cell-Free System , Drug Resistance, Multiple , Erythromycin/chemistry , Erythromycin/pharmacology , Haemophilus influenzae/drug effects , Lung/microbiology , Mice , Models, Molecular , Protein Biosynthesis , Protein Synthesis Inhibitors/chemistry , Protein Synthesis Inhibitors/pharmacology , Rats , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/mortality , Ribosomes/drug effects , Ribosomes/genetics , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/ultrastructure , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Transcription, Genetic
4.
Bioorg Med Chem ; 8(7): 1677-96, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10976515

ABSTRACT

The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungal Proteins , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Peptides , Acute Disease , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amphotericin B/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Candida/drug effects , Candidiasis, Vulvovaginal/drug therapy , Candidiasis, Vulvovaginal/microbiology , Disease Models, Animal , Dose-Response Relationship, Drug , Echinocandins , Female , Mice , Microbial Sensitivity Tests , Peptides, Cyclic/chemistry , Proline/chemistry , Solubility , Structure-Activity Relationship , Yeasts/drug effects
5.
Bioorg Med Chem Lett ; 10(13): 1405-8, 2000 Jul 03.
Article in English | MEDLINE | ID: mdl-10888319

ABSTRACT

Several 1,2,3,4-tetrahydro- and 7-N-hydroxycarbamate derivatives of the natural product rapamycin were prepared and assayed for their immunosuppressive and antifungal profiles. Substitutions at the 7-position indicate the possibility of a differentiated immunosuppressive to antifungal profile, whereas 40-position variants of the tetrahydro-analogues did not show similar differentiated activity.


Subject(s)
Antifungal Agents/pharmacology , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Animals , Antifungal Agents/chemistry , Biopharmaceutics , Candida/drug effects , Chemistry, Pharmaceutical , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Signal Transduction , Sirolimus/chemistry
6.
Antimicrob Agents Chemother ; 42(12): 3218-24, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9835517

ABSTRACT

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, 50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.


Subject(s)
Anti-HIV Agents/pharmacology , HIV Protease Inhibitors/pharmacology , Pyrimidinones/pharmacology , Animals , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacokinetics , Area Under Curve , Crystallography, X-Ray , Dogs , Drug Interactions , Female , HIV Protease/chemistry , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacokinetics , HIV-1/drug effects , Humans , In Vitro Techniques , Lopinavir , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Pyrimidinones/metabolism , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Ritonavir/chemistry , Ritonavir/pharmacology
7.
Virology ; 250(2): 255-62, 1998 Oct 25.
Article in English | MEDLINE | ID: mdl-9792836

ABSTRACT

The potency of therapeutic regimens containing human immunodeficiency virus (HIV) protease inhibitors is related to the ability to maintain concentrations of drug in the plasma of patients that are sufficient for blocking viral replication. The estimation of concentrations required for in vivo activity using in vitro assays is complicated by the fact that extensive binding of many protease inhibitors to serum proteins attenuates their antiviral potency. To provide insight into the relative in vivo potency of current protease inhibitors, we assayed their in vitro activity against wild-type and mutant HIV in the presence of human serum (HS). Using this assay, ABT-378, a new protease inhibitor with trough levels in humans far in excess of the EC50 in the presence of 50% HS, was identified. The antiviral activity of ABT-378 was only modestly attenuated by HS, in contrast to ritonavir, saquinavir, and nelfinavir. Examination of the effect of individual serum components suggested that the activity of ABT-378 is affected predominantly by binding to alpha1-acid glycoprotein (AGP) while the activity of ritonavir is modulated by both AGP and albumin. The method described here may provide insight into the in vivo potency of protease inhibitors and be useful for the preclinical evaluation and selection of new protease inhibitors for clinical studies.


Subject(s)
Blood Proteins/metabolism , HIV Protease Inhibitors/metabolism , HIV-1 , Mutation , Pyrimidinones/metabolism , Cell Line, Transformed , HIV Protease Inhibitors/pharmacology , HIV-1/genetics , Humans , Lopinavir , Ritonavir/metabolism
8.
J Med Chem ; 41(18): 3402-8, 1998 Aug 27.
Article in English | MEDLINE | ID: mdl-9719592

ABSTRACT

In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Erythromycin/analogs & derivatives , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Drug Design , Drug Stability , Duodenum/drug effects , Duodenum/physiology , Erythromycin/chemical synthesis , Erythromycin/chemistry , Erythromycin/metabolism , Erythromycin/pharmacology , Escherichia coli/drug effects , Hydrogen-Ion Concentration , In Vitro Techniques , Male , Models, Molecular , Molecular Conformation , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Pyloric Antrum/metabolism , Rabbits , Receptors, Gastrointestinal Hormone/metabolism , Receptors, Neuropeptide/metabolism , Staphylococcus aureus/drug effects , Stereoisomerism , Streptococcus/drug effects
9.
J Med Chem ; 41(10): 1651-9, 1998 May 07.
Article in English | MEDLINE | ID: mdl-9572890

ABSTRACT

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.


Subject(s)
Anti-Bacterial Agents , Carbamates , Erythromycin , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Clarithromycin/chemistry , Clarithromycin/pharmacology , Colony Count, Microbial , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Drug Resistance, Multiple , Erythromycin/analogs & derivatives , Erythromycin/chemical synthesis , Erythromycin/chemistry , Erythromycin/pharmacology , Haemophilus influenzae/drug effects , Lincosamides , Macrolides/pharmacology , Mice , Molecular Conformation , Pneumococcal Infections/prevention & control , Staphylococcal Infections/prevention & control , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Virginiamycin/pharmacology
10.
J Med Chem ; 41(10): 1660-70, 1998 May 07.
Article in English | MEDLINE | ID: mdl-9572891

ABSTRACT

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcuspneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.


Subject(s)
Anti-Bacterial Agents , Erythromycin/analogs & derivatives , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Clarithromycin/pharmacology , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Drug Resistance, Multiple , Erythromycin/chemical synthesis , Erythromycin/chemistry , Erythromycin/pharmacology , Lincosamides , Macrolides/pharmacology , Mice , Pneumococcal Infections/prevention & control , Staphylococcal Infections/prevention & control , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Virginiamycin/pharmacology
11.
J Med Chem ; 41(4): 602-17, 1998 Feb 12.
Article in English | MEDLINE | ID: mdl-9484509

ABSTRACT

The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/metabolism , Ritonavir/analogs & derivatives , Ritonavir/chemistry , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , HIV Protease/chemistry , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Metabolic Clearance Rate , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Conformation , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Ritonavir/pharmacokinetics , Ritonavir/pharmacology , Solubility , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 8(15): 1953-8, 1998 Aug 04.
Article in English | MEDLINE | ID: mdl-9873465

ABSTRACT

The 8-position side chain of 2-pyridones is believed to be involved in the binding with bacterial DNA gyrase to form the ternary complex, making them very important for the activity of 2-pyridones. A series of 2-pyridones having fluoro-substituted amines at the 8-position has been synthesized and their antibacterial activities and parmacokinetic properties are reported.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Pyridones/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Biological Availability , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Half-Life , Microbial Sensitivity Tests , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Structure-Activity Relationship
14.
Antimicrob Agents Chemother ; 41(3): 654-60, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9056009

ABSTRACT

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.


Subject(s)
Anti-HIV Agents/pharmacology , HIV Protease Inhibitors/pharmacokinetics , Ritonavir/pharmacology , Animals , Area Under Curve , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dogs , Drug Interactions , Female , HIV Protease Inhibitors/pharmacology , Humans , Male , Rats , Rats, Sprague-Dawley
16.
J Med Chem ; 39(16): 3070-88, 1996 Aug 02.
Article in English | MEDLINE | ID: mdl-8759628

ABSTRACT

Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Enzyme Inhibitors/chemical synthesis , Pyridones/chemical synthesis , Quinolizines/chemical synthesis , Topoisomerase II Inhibitors , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , DNA Topoisomerases, Type II/metabolism , DNA, Bacterial/metabolism , Drug Resistance, Microbial , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Quinolizines/chemistry , Quinolizines/pharmacokinetics , Quinolizines/pharmacology , Rats , Solubility , Structure-Activity Relationship
17.
Biochem Biophys Res Commun ; 225(2): 436-40, 1996 Aug 14.
Article in English | MEDLINE | ID: mdl-8753780

ABSTRACT

A series of novel, azacyclic ureas which are highly potent inhibitors of the HIV-1 protease (IC50 = 4.1 to < 0.5 nM) were synthesized. Aqueous solubilities of this series of compounds were improved by incorporating polar functional groups at the P1' P2 and P2' positions. These compounds also possess good anti-viral activity by inhibition of the cytopathic effect of HIV-13B in MT-4 cells in vitro.


Subject(s)
HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Urea/analogs & derivatives , Amino Acid Sequence , Animals , Biological Availability , Cell Line , HIV Protease/genetics , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacokinetics , Humans , Male , Molecular Sequence Data , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Urea/chemical synthesis , Urea/pharmacokinetics , Urea/pharmacology
18.
J Antibiot (Tokyo) ; 49(5): 465-77, 1996 May.
Article in English | MEDLINE | ID: mdl-8682724

ABSTRACT

The 11,12-cyclic carbazate of 3-keto-6-O-methylerythromycin A (4) was prepared. This compound shows in vitro antibacterial activity comparable to erythromycin A (1) against erythromycin-susceptible organisms and increased activity against some erythromycin-resistant organisms. Using 4 as a lead, a series of analogues was prepared by acylation or alkylation of the carbazate nitrogen. Several of the N-alkylated derivatives showed dramatically improved antibacterial activity against both susceptible and resistant organisms as compared to erythromycin A.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Erythromycin/pharmacology , Ketolides , Anti-Bacterial Agents/chemistry , Erythromycin/analogs & derivatives , Erythromycin/chemical synthesis , Erythromycin/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
20.
J Med Chem ; 39(2): 392-7, 1996 Jan 19.
Article in English | MEDLINE | ID: mdl-8558507

ABSTRACT

The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Binding Sites , Drug Resistance, Microbial , HIV Protease/metabolism , HIV-1/drug effects , Models, Molecular
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