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2.
J Med Chem ; 44(18): 3001-13, 2001 Aug 30.
Article in English | MEDLINE | ID: mdl-11520209

ABSTRACT

This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Aza Compounds/chemical synthesis , Azo Compounds/chemical synthesis , Imidazoles/chemical synthesis , Mesalamine/chemistry , Mesalamine/chemical synthesis , Platelet Activating Factor/antagonists & inhibitors , Prodrugs/chemical synthesis , Pyridines/chemical synthesis , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Aminosalicylic Acids , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , Azo Compounds/chemistry , Azo Compounds/pharmacokinetics , Azo Compounds/pharmacology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Drug Evaluation, Preclinical , Female , Hypotension/drug therapy , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Mesalamine/pharmacology , Platelet Aggregation/drug effects , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Trinitrobenzenesulfonic Acid
3.
J Med Chem ; 39(11): 2197-206, 1996 May 24.
Article in English | MEDLINE | ID: mdl-8667363

ABSTRACT

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.


Subject(s)
Angiotensin II/antagonists & inhibitors , Angiotensin Receptor Antagonists , Antihypertensive Agents/chemistry , Antihypertensive Agents/chemical synthesis , Imidazoles/chemistry , Imidazoles/chemical synthesis , Phenylpropionates/chemistry , Phenylpropionates/chemical synthesis , Administration, Oral , Adrenal Glands/metabolism , Angiotensin II/pharmacology , Animals , Antihypertensive Agents/pharmacology , Aorta, Thoracic , Biphenyl Compounds/chemistry , Blood Pressure/drug effects , Diet, Sodium-Restricted , Furosemide/pharmacology , Imidazoles/pharmacology , In Vitro Techniques , Indicators and Reagents , Kinetics , Liver/metabolism , Losartan , Male , Models, Molecular , Molecular Structure , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Phenylpropionates/pharmacology , Rabbits , Rats , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemistry
4.
J Med Chem ; 39(2): 487-93, 1996 Jan 19.
Article in English | MEDLINE | ID: mdl-8558517

ABSTRACT

Replacement of the polar head of our previous series of 1-acyl-4-[(2-methyl-3-pyridyl)-cyanomethyl]piperazines with a 2-methylimidazo[4,5-c]pyridine group has led to the identification of a new series of 1-[(1-acyl-4- piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor (PAF) antagonists. On the basis of the general structure--activity relationship trends found for the acyl substituent in our earlier series, five groups of compounds were tested, diaryl- or alkylarylpropanoyl derivatives, their 3-hydroxy-substituted analogues, and urea, carbamate and amino acid derivatives. The optimal compound 19 UR-12670), bearing the 3,3-diphenylpropanoyl moiety, exhibited very high in vitro and in vivo potency IC50 = 0.0076 microM for the in vitro PAF-induced platelet aggregation assay, ID50 = 0.0086 mg/kg for the in vivo PAF-induced hypotension test in normotensive rats, and ID50 = 0.092 mg/kg po and 0.0008 mg/kg i.v. for the PAF-induced mortality test in mice). Compound 19 also showed long duration of activity. It gave 100% protection against PAF-induced mortality in mice 7 h after i.v. administration of a single dose of 1 mg/kg and also provided 100% inhibition of PAF-induced aggregation in dog whole blood 6 h after i.v. administration of the same dose. The lead structure 19 has been selected for in-depth pharmacological evaluation.


Subject(s)
Imidazoles/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Dogs , Drug Design , Imidazoles/chemical synthesis , Imidazoles/chemistry , Magnetic Resonance Spectroscopy , Male , Mice , Platelet Activating Factor/pharmacology , Platelet Aggregation Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
5.
J Med Chem ; 37(17): 2697-703, 1994 Aug 19.
Article in English | MEDLINE | ID: mdl-7914928

ABSTRACT

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b, were prepared and evaluated for PAF antagonist and H1 antihistamine activity. PAF antagonist activity was investigated by the in vitro PAF-induced platelet aggregation assay (PPA) and the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) and the in vivo histamine-induced hypotension test (HH) in normotensive rats were used. The potential antiallergic activity of the compounds was evaluated using the active anaphylactic shock test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and H1 antihistamine activities have shown a high dependence on the exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity inhibiting both PAF-induced effects (PPA, IC50 = 3.7 microM; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passive cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and strongly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg po, and is now under development.


Subject(s)
Benzocycloheptenes/chemical synthesis , Histamine H1 Antagonists/chemical synthesis , Piperidines/chemical synthesis , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Anaphylaxis/prevention & control , Animals , Benzocycloheptenes/chemistry , Benzocycloheptenes/pharmacology , Blood Pressure/drug effects , Guinea Pigs , Histamine/pharmacology , Histamine H1 Antagonists/chemistry , Histamine H1 Antagonists/pharmacology , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Mice , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Piperidines/chemistry , Piperidines/pharmacology , Platelet Activating Factor/pharmacology , Platelet Activating Factor/toxicity , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
6.
J Med Chem ; 36(20): 2984-97, 1993 Oct 01.
Article in English | MEDLINE | ID: mdl-8411016

ABSTRACT

A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)-piperazines, with increased oral activity was prepared and evaluated in vitro in a PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP). Oral activity was ascertained through a PAF-induced mortality test in mice (MOR). Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test. Three different types of acyl substituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups. The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 microM, HYP, ID50 = 0.021 mg/kg i.v., MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 microM, HYP, ID50 = 0.015 mg/kg i.v., MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086. Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.


Subject(s)
Piperazines/chemical synthesis , Piperazines/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Anaphylaxis/drug therapy , Animals , Blood Pressure/drug effects , Endotoxins/toxicity , Escherichia coli , Male , Mice , Molecular Structure , Piperazines/therapeutic use , Platelet Activating Factor/pharmacology , Platelet Aggregation/drug effects , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
J Med Chem ; 36(15): 2121-33, 1993 Jul 23.
Article in English | MEDLINE | ID: mdl-8340916

ABSTRACT

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.


Subject(s)
Antihypertensive Agents/chemical synthesis , Benzopyrans/chemical synthesis , Naphthalenes/chemical synthesis , Potassium Channels/drug effects , Pyridones/chemical synthesis , Animals , Benzopyrans/pharmacology , Blood Pressure/drug effects , Guinea Pigs , Male , Naphthalenes/pharmacology , Pyridones/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Trachea/drug effects
8.
J Med Chem ; 35(22): 4118-34, 1992 Oct 30.
Article in English | MEDLINE | ID: mdl-1433215

ABSTRACT

A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.


Subject(s)
Piperazines/chemical synthesis , Piperidines/chemical synthesis , Platelet Activating Factor/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Blood Pressure/drug effects , In Vitro Techniques , Male , Mice , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Piperidines/pharmacology , Platelet Aggregation/drug effects , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
9.
J Med Chem ; 35(4): 676-83, 1992 Feb 21.
Article in English | MEDLINE | ID: mdl-1542094

ABSTRACT

A series of 4-substituted 2-alkoxytetrahydrofuran derivatives featuring an acetal group were prepared and evaluated for PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Compound 2-[[N-acetyl-N-[[[2-(octadecyloxy)tetrahydrofuran-4- yl]methoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (4e, UR-11353) was selected for further development on the basis of its high activity and long-lasting action. The compound maintained a significant activity even 24 h after administration of a single dose of 1 mg/kg iv in the PAF-induced mortality test in mice and 10 h after administration of the same dose in the PAF-induced hypotension test in rats. Comparison with previously reported carba analogues suggests that the presence of the acetal group is the structural characteristic that confers its long-lasting activity.


Subject(s)
Furans/chemistry , Furans/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemistry , Pyridinium Compounds/pharmacology , Animals , Hypotension/chemically induced , Hypotension/prevention & control , Male , Mice , Molecular Structure , Platelet Activating Factor/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Pyridinium Compounds/chemistry , Rabbits , Rats , Rats, Inbred Strains
11.
J Med Chem ; 34(1): 373-86, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1992139

ABSTRACT

A new series of disubstituted tetrahydrofuran and dioxolane derivatives were prepared and evaluated for their PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Several of these compounds exhibited more potent activity than the structurally related 2-[N-acetyl-N-[[[[2-methoxy-3-[(octadecylcarbamoyl) oxy]propoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (CV-6209, 3) in the in vitro assay, whereas all showed less potency in the in vivo test. The role of both the substituent nature and the placement and number of oxygen atoms in the ring are discussed. A quantitative SAR study carried out on these nuclei.


Subject(s)
Blood Pressure/drug effects , Dioxolanes/chemical synthesis , Furans/chemical synthesis , Furans/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Animals , Dioxolanes/chemistry , Dioxolanes/pharmacology , Furans/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Molecular Structure , Rabbits , Rats , Rats, Inbred Strains , Structure-Activity Relationship
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