Search

Your search keyword '"McDonnell M"' showing total 8 results
Start Over Author "McDonnell M" Journal journal of medicinal chemistry
8 results on '"McDonnell M"'

1. Design and Synthesis of Thrombin Inhibitors: Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

Author

Graham Arton Howarth, Talbot, Judy Hayler, Garrick Smith, Derek E. Brundish, Wakeford R, John Ambler, Mark C. Allen, Joseph D. Fullerton, Peter D. Kane, Christoph Walker, Sheila Garman, Donovan, Bull A, K D Butler, William Hoyle, Diana Janus, and McDonnell M

Subjects
Models, Molecular, Stereochemistry, medicine.drug_class, Injections, Subcutaneous, Carboxamide, Arginine, Chemical synthesis, Antithrombins, Stereocenter, Structure-Activity Relationship, Thrombin, Piperidines, Drug Discovery, medicine, Animals, Humans, Potency, Sulfonamides, biology, Chemistry, Enantioselective synthesis, Stereoisomerism, Thrombosis, Rats, Enzyme inhibitor, Drug Design, Pipecolic Acids, Injections, Intravenous, biology.protein, Molecular Medicine, Cattle, medicine.drug, Discovery and development of direct thrombin inhibitors
Abstract

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

Published
1999

3. Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

Author

Brundish, D., Bull, A., Donovan, V., Fullerton, J. D., Garman, S. M., Hayler, J. F., Janus, D., Kane, P. D., McDonnell, M., Smith, G. P., Wakeford, R., Walker, C. V., Howarth, G., Hoyle, W., Allen, M. C., Ambler, J., Butler, K., and Talbot, M. D.

Abstract

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a Ki of 6 nM (MD-805 Ki = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

Published
1999

4. Orally Active Benzamide Antipsychotic Agents with Affinity for Dopamine D<INF>2</INF>, Serotonin 5-HT<INF>1A</INF>, and Adrenergic α<INF>1</INF> Receptors

Author

Reitz, A. B., Baxter, E. W., Codd, E. E., Davis, C. B., Jordan, A. D., Maryanoff, B. E., Maryanoff, C. A., McDonnell, M. E., Powell, E. T., Renzi, M. J., Schott, M. R., Scott, M. K., Shank, R. P., and Vaught, J. L.

Abstract

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and α1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Published
1998

5. Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.

Author

Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, and Reitz AB

Subjects
Adrenergic alpha-Agonists chemistry, Adrenergic alpha-Agonists pharmacology, Analgesics chemical synthesis, Analgesics chemistry, Analgesics pharmacology, Animals, Binding, Competitive, Cell Line, Humans, Imidazoles chemistry, Imidazoles pharmacology, Ligands, Mice, Pain Measurement, Radioligand Assay, Rats, Receptors, Adrenergic, alpha-2 metabolism, Structure-Activity Relationship, Thiophenes chemistry, Thiophenes pharmacology, Adrenergic alpha-Agonists chemical synthesis, Imidazoles chemical synthesis, Receptors, Adrenergic, alpha-2 drug effects, Thiophenes chemical synthesis
Published
2000
Full Text
View/download PDF

6. alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.

Author

Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, and Reitz AB

Subjects
Administration, Oral, Adrenergic alpha-Agonists chemistry, Adrenergic alpha-Agonists metabolism, Adrenergic alpha-Agonists pharmacology, Analgesics, Non-Narcotic chemistry, Analgesics, Non-Narcotic metabolism, Analgesics, Non-Narcotic pharmacology, Animals, Binding, Competitive, Cell Line, Imidazoles chemistry, Imidazoles metabolism, Imidazoles pharmacology, In Vitro Techniques, Mice, Rats, Receptors, Adrenergic, alpha-2 metabolism, Structure-Activity Relationship, Thiophenes chemistry, Thiophenes metabolism, Thiophenes pharmacology, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists chemical synthesis, Analgesics, Non-Narcotic chemical synthesis, Imidazoles chemical synthesis, Thiophenes chemical synthesis
Published
2000
Full Text
View/download PDF

7. Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alpha1 receptors.

Author

Reitz AB, Baxter EW, Codd EE, Davis CB, Jordan AD, Maryanoff BE, Maryanoff CA, McDonnell ME, Powell ET, Renzi MJ, Schott MR, Scott MK, Shank RP, and Vaught JL

Subjects
Adrenergic Agents chemical synthesis, Adrenergic Agents chemistry, Adrenergic Agents metabolism, Adrenergic Agents pharmacology, Animals, Avoidance Learning drug effects, Catalepsy chemically induced, Cerebral Cortex metabolism, Conditioning, Psychological drug effects, Corpus Striatum metabolism, Dopamine Agents chemical synthesis, Dopamine Agents chemistry, Dopamine Agents metabolism, Dopamine Agents pharmacology, Humans, Male, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptors, Serotonin, 5-HT1, Serotonin Agents chemical synthesis, Serotonin Agents chemistry, Serotonin Agents metabolism, Serotonin Agents pharmacology, Structure-Activity Relationship, Antipsychotic Agents chemical synthesis, Antipsychotic Agents chemistry, Antipsychotic Agents metabolism, Antipsychotic Agents pharmacology, Piperazines chemical synthesis, Piperazines chemistry, Piperazines metabolism, Piperazines pharmacology, Piperidines chemical synthesis, Piperidines chemistry, Piperidines metabolism, Piperidines pharmacology, Receptors, Adrenergic, alpha-1 metabolism, Receptors, Dopamine D2 metabolism, Receptors, Serotonin metabolism
Abstract

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Published
1998
Full Text
View/download PDF

8. N-aryl-N'-benzylpiperazines as potential antipsychotic agents.

Author

Reitz AB, Baxter EW, Bennett DJ, Codd EE, Jordan AD, Malloy EA, Maryanoff BE, McDonnell ME, Ortegon ME, and Renzi MJ

Subjects
Animals, Antipsychotic Agents metabolism, Antipsychotic Agents pharmacology, Avoidance Learning drug effects, Cell Membrane metabolism, Cerebral Cortex metabolism, Conditioning, Psychological drug effects, Male, Molecular Structure, Piperazines metabolism, Piperazines pharmacology, Piperidones metabolism, Piperidones pharmacology, Rats, Rats, Wistar, Receptors, Adrenergic, alpha metabolism, Receptors, Dopamine D2 metabolism, Receptors, Serotonin metabolism, Structure-Activity Relationship, Antipsychotic Agents chemical synthesis, Piperazines chemical synthesis, Piperidones chemical synthesis
Abstract

N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.

Published
1995
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results