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1.
Drug Metab Dispos ; 29(1): 1-3, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11124221

ABSTRACT

More than 60 human immunodeficiency virus protease inhibitors were examined for the structure-activity relationship between metabolic stability, CYP3A4 inhibitory potency, and substrate-induced binding spectra with a ferric form of P450 in human liver microsomes. A positive relationship was found between CYP3A4 inhibitory potency and metabolic stability; namely, compounds that were more potent for the CYP3A4 inhibition generally were more metabolically stable. In addition, the compounds formed two clusters defined by the distinct type of substrate-induced P450 binding spectra: the compounds with type II binding spectra were more stable metabolically and more potent for the CYP3A4 inhibition than those with type I binding spectra. The structure-activity relationship suggested that the presence and position of heterocyclic nitrogen on the pyridine moiety play an important role in determining the manner of interaction with P450 and the magnitude of CYP3A4 inhibition/metabolic stability in the series of structurally related human immunodeficiency virus protease inhibitors under development.


Subject(s)
Anti-HIV Agents/metabolism , Cytochrome P-450 Enzyme System/metabolism , HIV Protease Inhibitors/metabolism , Mixed Function Oxygenases/metabolism , Anti-HIV Agents/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , HIV Protease Inhibitors/pharmacology , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Mixed Function Oxygenases/antagonists & inhibitors , Protein Binding , Structure-Activity Relationship
2.
J Med Chem ; 43(18): 3386-99, 2000 Sep 07.
Article in English | MEDLINE | ID: mdl-10978186

ABSTRACT

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.


Subject(s)
Antiviral Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Indans/chemical synthesis , Piperazines/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cattle , Cell Culture Techniques , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Haplorhini , Humans , Indans/chemistry , Indans/pharmacokinetics , Indans/pharmacology , Male , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Urinary Calculi/chemically induced , Urinary Calculi/urine
3.
Curr Opin Chem Biol ; 4(4): 394-400, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10959766

ABSTRACT

The search for the ideal anticoagulant has spanned decades and has resulted in several strategies including the clinical use of heparin, low molecular weight heparins, and the vitamin K antagonist warfarin. Over the past five years, many groups have reported preclinical results with direct-acting thrombin inhibitors and several of these are now moving into clinical trials. In addition, many groups have disclosed the discovery of potent, orally bioavailable factor Xa inhibitors. Several of these compounds are now in early clinical trials and the results are forthcoming.


Subject(s)
Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Antithrombins/pharmacology , Factor Xa Inhibitors , Thrombolytic Therapy , Animals , Antithrombins/therapeutic use , Humans , In Vitro Techniques , Molecular Structure , Rats
6.
J Med Chem ; 42(12): 2180-90, 1999 Jun 17.
Article in English | MEDLINE | ID: mdl-10377223

ABSTRACT

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.


Subject(s)
Aminopyridines/chemical synthesis , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Mitogen-Activated Protein Kinases , Administration, Oral , Aminopyridines/chemistry , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Arthritis, Experimental/drug therapy , Biological Availability , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Macaca mulatta , Mice , Rats , Stimulation, Chemical , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases
7.
J Pharmacol Exp Ther ; 289(1): 503-10, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10087043

ABSTRACT

The small molecule direct thrombin inhibitor L-374,087 was characterized across species in an in vitro activated partial thromboplastin clotting time (aPTT) assay and in vivo in rhesus monkey and dog thrombosis models. In vitro in rhesus, dog, and human plasma, L-374,087 concentrations eliciting 2-fold increases in aPTT were 0.25, 1.9, and 0.28 microM, respectively. In anesthetized rhesus monkeys, 300 microgram/kg bolus plus 12 microgram/kg/min and 300 microgram/kg bolus plus 30 microgram/kg/min L-374,087 i.v. infusions significantly reduced jugular vein thrombus extension, with both regimens limiting venous thrombus extension to 2-fold that of baseline thrombus mass compared with a 5-fold extension observed in the vehicle control group. Antithrombotic efficacy in the rhesus with the lower-dose regimen was achieved with 2.3- to 2.4-fold increases in aPTT and prothrombin time. In a conscious instrumented dog model of electrolytic vessel injury, the oral administration of two 10 mg/kg L-374,087 doses 12 h apart significantly reduced jugular vein thrombus mass, reduced the incidence of and delayed time to occlusive coronary artery thrombosis, and significantly reduced coronary artery thrombus mass and ensuing posterolateral myocardial infarct size. Antithrombotic efficacy in the dog was achieved with 1.6- to 2.0-fold increases in aPTT at 1 to 6 h after oral dosing with L-374,087. These results indicate significant antithrombotic efficacy against both venous and coronary arterial thrombosis with L-374,087 with only moderate elevations in aPTT or prothrombin time. The oral efficacy of L-374,087 characterizes this compound as a prototype for the further development of orally active direct thrombin inhibitors.


Subject(s)
Coronary Thrombosis/drug therapy , Fibrinolytic Agents/pharmacology , Jugular Veins/pathology , Pyridones/pharmacology , Sulfonamides/pharmacology , Thrombin/antagonists & inhibitors , Venous Thrombosis/drug therapy , Administration, Oral , Anesthesia , Animals , Bleeding Time , Blood Coagulation/drug effects , Coronary Thrombosis/blood , Dogs , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacokinetics , Hematocrit , Hemoglobins/metabolism , Humans , In Vitro Techniques , Injections, Intravenous , Macaca mulatta , Male , Partial Thromboplastin Time , Platelet Count/drug effects , Pyridones/administration & dosage , Pyridones/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Venous Thrombosis/blood
8.
J Med Chem ; 41(23): 4466-74, 1998 Nov 05.
Article in English | MEDLINE | ID: mdl-9804686

ABSTRACT

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.


Subject(s)
Aminopyridines/chemical synthesis , Peptides/chemistry , Pyrazines/chemical synthesis , Pyridones/chemical synthesis , Thrombin/antagonists & inhibitors , Aminopyridines/chemistry , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Macaca mulatta , Models, Molecular , Molecular Mimicry , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Structure-Activity Relationship
10.
Biochem Pharmacol ; 56(2): 223-30, 1998 Jul 15.
Article in English | MEDLINE | ID: mdl-9698076

ABSTRACT

P450 complex formation and the unusual pharmacokinetics of methylenedioxyphenyl HIV protease inhibitors were examined by in vitro studies using human and rat liver microsomes and by in vivo oral dosing studies. In vitro spectral studies indicated that the formation of a P450 complex having absorbance maxima at 425 and 456 nm was time and concentration dependent; 27-60% of the total P450 was complexed in dexamethasone-induced rat liver microsomes after a 30-min incubation with 100 microM HIV protease inhibitors. Methoxy substitution on the phenyl ring of the methylenedioxyphenyl moiety increased formation of the P450 complex, whereas chlorine substitution markedly decreased the P450 complexation. Kinetic studies on the P450 complex formation indicated that both methoxy and chlorine substitution affected the maximum complex formation rate (Vmax), while it had little effect on Km values (approximately 10 microM). This complexation in human liver microsomes was inhibited markedly by an anti-CYP3A1 antibody. Furthermore, the P450 complex formation resulted in a time-dependent loss of CYP3A-catalyzed marker activities (testosterone 2beta/6beta-hydroxylase) in both rat and human liver microsomes. Collectively, these results point to the involvement of CYP3A isoforms in P450 complexation by methylenedioxyphenyl HIV protease inhibitors. Additionally, after oral administration to rats, one of these HIV protease inhibitors (Compound I), which complexed P450 to the greatest extent, showed no elimination over a period of 500 min after administration of the highest dose. It is suggested that formation of a quasi-irreversible metabolite-CYP3A complex with methylenedioxyphenyl HIV protease inhibitors was responsible for the CYP3A-selective time-dependent loss of catalytic function and the unusual dose-dependent pharmacokinetics after oral administration.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/metabolism , HIV Protease Inhibitors/pharmacology , Isoenzymes/metabolism , Microsomes, Liver/drug effects , Animals , Biotransformation , Catalysis , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacokinetics , Half-Life , Humans , Hydroxylation , Male , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley
11.
J Med Chem ; 41(17): 3210-9, 1998 Aug 13.
Article in English | MEDLINE | ID: mdl-9703466

ABSTRACT

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.


Subject(s)
Cyclohexylamines/chemical synthesis , Dipeptides/chemical synthesis , Fibrinolytic Agents/chemical synthesis , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Binding Sites , Biological Availability , Computer Simulation , Crystallography, X-Ray , Cyclohexylamines/chemistry , Cyclohexylamines/pharmacokinetics , Dipeptides/chemistry , Dipeptides/pharmacokinetics , Dogs , Drug Design , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Hydrogen Bonding , Macaca fascicularis , Models, Molecular , Molecular Conformation , Molecular Structure , Rats , Resins, Plant , Structure-Activity Relationship , Thrombin/chemistry
12.
J Med Chem ; 41(7): 1011-3, 1998 Mar 26.
Article in English | MEDLINE | ID: mdl-9544200

ABSTRACT

Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.


Subject(s)
Antithrombins/chemical synthesis , Benzhydryl Compounds/chemical synthesis , Pyrroles/chemical synthesis , Thrombin/antagonists & inhibitors , Antithrombins/chemistry , Benzhydryl Compounds/chemistry , Drug Design , Models, Molecular , Pyrroles/chemistry , Structure-Activity Relationship
13.
J Med Chem ; 41(3): 401-6, 1998 Jan 29.
Article in English | MEDLINE | ID: mdl-9464370

ABSTRACT

Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.


Subject(s)
Antithrombins/chemistry , Drug Design , Pyrrolidines/chemistry , Animals , Antithrombins/pharmacokinetics , Antithrombins/pharmacology , Biological Availability , Dogs , Haplorhini , Models, Molecular , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 8(13): 1697-702, 1998 Jul 07.
Article in English | MEDLINE | ID: mdl-9873418

ABSTRACT

A novel, nonpeptidyl thrombin inhibitor, L-636,619 (1), was identified via topological similarity searching over the Merck Corporate Sample Database. X-ray crystallographic studies determined the geometry for ligand binding to the enzyme. Chemical modification of the P1 and P3 segments of the ligand resulted in enhanced potency and improvement in the chemical stability of the lead. Analog 9 proved to be the most interesting lead from this structurally novel series.


Subject(s)
Antithrombins/chemistry , Antithrombins/pharmacology , Binding Sites , Crystallography , Models, Molecular , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 8(13): 1719-24, 1998 Jul 07.
Article in English | MEDLINE | ID: mdl-9873422

ABSTRACT

1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.


Subject(s)
Antithrombins/chemistry , Antithrombins/pharmacokinetics , Pyridones/chemistry , Pyridones/pharmacokinetics , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Antithrombins/administration & dosage , Biological Availability , Dogs , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyridones/pharmacology , Rats , Sulfanilamides/chemistry , Sulfanilamides/pharmacokinetics , Sulfanilamides/pharmacology , Sulfonamides/pharmacology
16.
Bioorg Med Chem Lett ; 8(7): 817-22, 1998 Apr 07.
Article in English | MEDLINE | ID: mdl-9871547

ABSTRACT

Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.


Subject(s)
Anticoagulants/pharmacology , Pyridones/pharmacology , Sulfonamides/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/chemistry , Biological Availability , Chlorides , Crystallography, X-Ray , Dogs , Ferric Compounds , Kinetics , Macaca fascicularis , Models, Molecular , Molecular Structure , Pyridones/administration & dosage , Pyridones/chemistry , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistry , Thrombosis/drug therapy , Trypsin/metabolism
17.
J Med Chem ; 40(23): 3726-33, 1997 Nov 07.
Article in English | MEDLINE | ID: mdl-9371237

ABSTRACT

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.


Subject(s)
Antithrombins/chemical synthesis , Antithrombins/pharmacology , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Antithrombins/pharmacokinetics , Biological Availability , Crystallography, X-Ray , Dipeptides/pharmacokinetics , Dogs , Kinetics , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Thrombin/metabolism
18.
J Med Chem ; 40(22): 3687-93, 1997 Oct 24.
Article in English | MEDLINE | ID: mdl-9357536

ABSTRACT

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.


Subject(s)
Propionates/chemical synthesis , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Dogs , Magnetic Resonance Spectroscopy , Propionates/pharmacokinetics , Propionates/pharmacology , Rats , Spectrometry, Mass, Fast Atom Bombardment
19.
J Med Chem ; 40(11): 1565-9, 1997 May 23.
Article in English | MEDLINE | ID: mdl-9171866

ABSTRACT

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.


Subject(s)
Dipeptides/chemical synthesis , Fibrinolytic Agents/chemical synthesis , Phenylalanine/analogs & derivatives , Thrombin/antagonists & inhibitors , Animals , Biological Availability , Dipeptides/pharmacokinetics , Dipeptides/therapeutic use , Dogs , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/therapeutic use , Lipid Metabolism , Male , Molecular Structure , Partial Thromboplastin Time , Phenylalanine/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thrombosis/drug therapy
20.
J Med Chem ; 38(2): 305-17, 1995 Jan 20.
Article in English | MEDLINE | ID: mdl-7830273

ABSTRACT

We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , Binding Sites , Computer-Aided Design , Drug Design , HIV Protease/ultrastructure , Models, Molecular , Protein Structure, Tertiary , Structure-Activity Relationship , Thermodynamics
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