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2.
J Med Chem ; 41(12): 2146-63, 1998 Jun 04.
Article in English | MEDLINE | ID: mdl-9622556

ABSTRACT

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.


Subject(s)
Oxazines , Pyridines , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Line , Chromatography, High Pressure Liquid , Dogs , Female , Humans , Kidney/cytology , Kidney/embryology , Kidney/metabolism , Liver/metabolism , Male , Mass Spectrometry , Oxazines/chemical synthesis , Oxazines/metabolism , Oxazines/pharmacokinetics , Oxazines/pharmacology , Pregnancy , Pyridines/chemical synthesis , Pyridines/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Receptors, Oxytocin/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Spectrophotometry, Ultraviolet , Uterine Contraction/drug effects , Uterus/drug effects , Uterus/physiology
3.
Bioorg Med Chem Lett ; 8(18): 2467-72, 1998 Sep 22.
Article in English | MEDLINE | ID: mdl-9873563

ABSTRACT

Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists , Adrenergic alpha-Antagonists/chemical synthesis , Drug Design , Saccharin/analogs & derivatives , Adrenergic alpha-Antagonists/pharmacology , Alkylation , Animals , Aorta/drug effects , CHO Cells , Cell Line , Cricetinae , Dogs , Finasteride/chemistry , Finasteride/pharmacology , Humans , In Vitro Techniques , Male , Models, Chemical , Prazosin/analogs & derivatives , Prazosin/chemistry , Prazosin/pharmacology , Prostate/drug effects , Rats , Receptors, Adrenergic, alpha-1 , Saccharin/chemical synthesis , Saccharin/pharmacology , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Tamsulosin
4.
J Med Chem ; 37(21): 3443-51, 1994 Oct 14.
Article in English | MEDLINE | ID: mdl-7932573

ABSTRACT

A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Animals , Binding, Competitive , Biological Availability , Cell Line , Crystallography, X-Ray , Dogs , Drug Design , HIV Protease/metabolism , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , HIV-1/growth & development , HIV-2/enzymology , Humans , Indinavir , Models, Molecular , Molecular Structure , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , T-Lymphocytes/virology
5.
Bioorg Med Chem ; 2(9): 859-79, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7712123

ABSTRACT

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , Lactams/chemical synthesis , Lactams/pharmacology , Administration, Oral , Animals , Biological Availability , Chemical Phenomena , Chemistry, Physical , Dogs , HIV Protease Inhibitors/pharmacokinetics , HIV-1/drug effects , HIV-1/enzymology , Humans , Lactams/pharmacokinetics , Male , Models, Molecular , Structure-Activity Relationship
6.
J Med Chem ; 34(9): 2852-7, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1910089

ABSTRACT

A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.


Subject(s)
Antiviral Agents , HIV Protease Inhibitors , Oligopeptides/pharmacology , Viral Proteins , Antiviral Agents/chemical synthesis , Drug Design , Gene Products, gag/analysis , HIV Antigens/analysis , HIV Core Protein p24 , HIV-1/drug effects , HIV-1/enzymology , HIV-1/isolation & purification , HIV-1/physiology , Humans , Oligopeptides/chemistry , Protein Precursors/analysis , T-Lymphocytes/microbiology , Viral Core Proteins/analysis , Virus Replication/drug effects , gag Gene Products, Human Immunodeficiency Virus
10.
Naunyn Schmiedebergs Arch Pharmacol ; 338(1): 47-52, 1988 Jul.
Article in English | MEDLINE | ID: mdl-2907099

ABSTRACT

L-654,284 [2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide], a potent and selective antagonist of the alpha 2 adrenoceptor, was tritiated to high specific activity. Saturation binding to cell membrane suspensions obtained from calf cerebral cortex revealed a high affinity binding site (0.63 nM). Kinetics of association and dissociation were well represented by single exponential processes, and the equilibrium dissociation constant obtained from the ratio of rate constants agreed well with that found by saturation binding. A direct comparison of saturation binding revealed that the antagonist [3H]L-654,284 had roughly the same affinity for the alpha 2 adrenoceptor as the agonist [3H]clonidine and eight times the affinity of the antagonist [3H]rauwolscine. The maximum receptor densities of these radioligands were not significantly different. Competition assays with a series of compounds of known receptor affinity revealed that [3H]L-654,284 selectively binds to a site with all of the characteristics expected of the alpha 2 adrenoceptor.


Subject(s)
Adrenergic alpha-Antagonists , Quinolizines , Receptors, Adrenergic, alpha/drug effects , Animals , Binding, Competitive/drug effects , Cattle , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Clonidine/metabolism , In Vitro Techniques , Radioligand Assay , Yohimbine/metabolism
11.
J Med Chem ; 31(3): 641-5, 1988 Mar.
Article in English | MEDLINE | ID: mdl-2831365

ABSTRACT

Hexahydroaryl[a]quinolizines comprise a prominent structural element in several alpha 2-adrenoceptor antagonists. Eight hexahydroheteroarylquinolizines were prepared as minimal ligands to investigate the relationship between the nature of the aromatic ring and affinity of these molecules for alpha-adrenoceptors. Affinity for alpha 1-and alpha 2-adrenoceptors was assessed by displacement of [3H]prasozin and [3H]clonidine, respectively. Lipophilicity of the aryl portion of the molecules, reflected by their partition coefficient between octanol and pH 7.4 buffer, correlated well with affinity at both receptor subtypes. Although some compounds showed nanomolar affinity for alpha-adrenoceptors, no subtype selectivity was observed. These results suggest that the aromatic ring enhances binding at both receptors chiefly through hydrophobic interactions and contributes little to subtype selectivity.


Subject(s)
Quinolizines/metabolism , Receptors, Adrenergic, alpha/metabolism , Algorithms , Animals , Binding, Competitive , Cattle , Clonidine/metabolism , Hydrogen-Ion Concentration , Prazosin/metabolism , Structure-Activity Relationship , Yohimbine/metabolism
13.
J Med Chem ; 27(9): 1182-5, 1984 Sep.
Article in English | MEDLINE | ID: mdl-6088770

ABSTRACT

A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.


Subject(s)
Pyridines/pharmacology , Receptors, Adrenergic, alpha/metabolism , Tetrabenazine/antagonists & inhibitors , Animals , Blepharoptosis/drug therapy , Cerebral Cortex/metabolism , Clonidine/antagonists & inhibitors , Male , Methoxamine/antagonists & inhibitors , Mice , Pyridines/chemical synthesis , Rats , Structure-Activity Relationship
14.
J Med Chem ; 26(12): 1696-701, 1983 Dec.
Article in English | MEDLINE | ID: mdl-6139479

ABSTRACT

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.


Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Piperazines/chemical synthesis , Pyridines/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Animals , Cats , Clonidine/antagonists & inhibitors , Male , Muscle Contraction/drug effects , Piperazines/pharmacology , Pupil/drug effects , Pyridines/pharmacology , Rats , Vas Deferens/drug effects , Yohimbine/pharmacology
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