(S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl]benzenesulfonamide, a selective dopamine D4 antagonist

Journal of Medicinal Chemistry

Volumn 39, Issue 13, 1996, Pages 2435-2437

  TenBrink, Ruth E ^a,b   Bergh, Carol L ^a,b   Duncan, J Neil ^a,c   Harris, Douglas W ^a,d   Huff, R M ^a,e   Lahti, Robert A ^a,f   Lawson, Charles F ^a,g   Lutzke, Barry S ^a,g   Martin, Iain J ^a,c   Rees, Susan A ^a,c   Schlachter, Siusaidh K ^a,g   Sih, John C ^a,h   Smith, Martin W ^a,g  

^a PFIZER INC   (United States)

^b Innovative Analytics   (United States)

^c Metabolism and Pharmacokinetics   (United Kingdom)

^d Cardiovasc Pharmacol Pharmacia/U   (United States)

^e CNS Diseases Research   (United States)

^f MARYLAND PSYCHIATRIC RESEARCH CENTER   (United States)

^g Chemical and Biological Screening   (United States)

^h Chemical Process R and D   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 DIPROPYLAMINO 8 HYDROXYTETRALIN; 4 [4 [2 (1 ISOCHROMANYL)ETHYL] 1 PIPERAZINYL]BENZENESULFONAMIDE; 8 CHLORO 2,3,4,5 TETRAHYDRO 3 METHYL 5 PHENYL 1H 3 BENZAZEPIN 7 OL HYDROGEN MALEATE; BUTACLAMOL; CLONIDINE; CLOZAPINE; DOPAMINE 4 RECEPTOR; DOPAMINE RECEPTOR BLOCKING AGENT; EMONAPRIDE; ISOCHROMAN DERIVATIVE; KETANSERIN; LIGAND; PRAZOSIN; QUINPIROLE; SONEPIPRAZOLE; SPIPERONE; SULFONAMIDE; U 86170; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; MONKEY; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; SCHIZOPHRENIA;

ANIMALS; ANTIPSYCHOTIC AGENTS; BIOLOGICAL AVAILABILITY; CHO CELLS; CRICETINAE; DOPAMINE AGONISTS; DOPAMINE ANTAGONISTS; ERGOLINES; HUMANS; MOLECULAR STRUCTURE; PIPERAZINES; PROTEIN BINDING; QUINPIROLE; RECEPTORS, ADRENERGIC; RECEPTORS, DOPAMINE D2; RECEPTORS, DOPAMINE D4; RECEPTORS, SEROTONIN; SCHIZOPHRENIA; SULFONAMIDES;

EID: 0029941536     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960084f     Document Type: Article

References (27)

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11. (b) Assay: ICE was partially purified from THP-1 cells using the DEAE-Sephacel and Sephadex G-75 steps described by Black (Black, R. A.; Kronheim, S. R.; Sleath, P. R. Activation of Interluekin-1β by a Co-induced Protease. FEBS Lett. 1989, 247, 386). The ICE assay contained 10 mM HEPES (pH 7.5), 25% glycerol, 1 mM dithiotreitol (DTT), and 10 μM Suc-Tyr-Val-Ala-Asp-AMC (BACHEM) in a volume of 30 μL in a polystyrene 96-well microtiter plate. Progress curves were obtained at 37°C over 30 min. Kinetic data were obtained on a Fluoroskan II fluorescence plate reader under control of an Apple Macintosh computer running the DeltaSoft data aquisition program (Biometallics, Inc.). Nonlinear progress curves were analyzed as described by Tian and Tsou (Tian, W.-X.; Tsou, C.-L. Determination of the Rate Constant of Enzyme Modification by Measuring the Substrate Reaction in the Presence of the Modifier. Biochemistry 1982, 21, 1028-1032).
12. (b) Assay: ICE was partially purified from THP-1 cells using the DEAE-Sephacel and Sephadex G-75 steps described by Black (Black, R. A.; Kronheim, S. R.; Sleath, P. R. Activation of Interluekin-1β by a Co-induced Protease. FEBS Lett. 1989, 247, 386). The ICE assay contained 10 mM HEPES (pH 7.5), 25% glycerol, 1 mM dithiotreitol (DTT), and 10 μM Suc-Tyr-Val-Ala-Asp-AMC (BACHEM) in a volume of 30 μL in a polystyrene 96-well microtiter plate. Progress curves were obtained at 37°C over 30 min. Kinetic data were obtained on a Fluoroskan II fluorescence plate reader under control of an Apple Macintosh computer running the DeltaSoft data aquisition program (Biometallics, Inc.). Nonlinear progress curves were analyzed as described by Tian and Tsou (Tian, W.-X.; Tsou, C.-L. Determination of the Rate Constant of Enzyme Modification by Measuring the Substrate Reaction in the Presence of the Modifier. Biochemistry 1982, 21, 1028-1032).
13. 3 Amido Nitrogens For Enzyme-Peptide Inhibitor Binding. J. Med. Chem. 1994, 37, 3863-3865.
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15. (a) Wilson, K. P.; Black, J. F.; Thompson, J. A.; Kim, E. E.; Griffith, J. P.; Navia, M. A.; Murcko, M. A.; Chambers, S. P.; Aldape, R. A.; Raybuck, S. A.; Livingston, D. J. Structure and Mechanism of Interleukin-1β Converting Enzyme. Nature 1994, 370, 270-252.
16. 2 Homodimer. Cell 1994, 78, 343-352.
17. 3. See: (a) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Pyrimidinyl Acetamides as Elastase Inhibitors. European Patent Application, publication no. WO 9321210, October 1993. (b) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Shenvi, A. B.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Alpha-Aminoboronic Acid Peptides and Their Use as Elastase Inhibitors. PTC publication no. WO 9321214, October 1993. (c) Veale, C. A.; Steelman, G. B.; Chow, M. M. Efficient Method for the Synthesis of 1,4-Disubstituted 5-Carbomethoxy-pyrimidin-6-ones. J. Org. Chem. 1993, 58, 4490-4493. (d) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 1259-1261.
18. 3. See: (a) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Pyrimidinyl Acetamides as Elastase Inhibitors. European Patent Application, publication no. WO 9321210, October 1993. (b) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Shenvi, A. B.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Alpha-Aminoboronic Acid Peptides and Their Use as Elastase Inhibitors. PTC publication no. WO 9321214, October 1993. (c) Veale, C. A.; Steelman, G. B.; Chow, M. M. Efficient Method for the Synthesis of 1,4-Disubstituted 5-Carbomethoxy-pyrimidin-6-ones. J. Org. Chem. 1993, 58, 4490-4493. (d) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 1259-1261.
19. 3. See: (a) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Pyrimidinyl Acetamides as Elastase Inhibitors. European Patent Application, publication no. WO 9321210, October 1993. (b) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Shenvi, A. B.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Alpha-Aminoboronic Acid Peptides and Their Use as Elastase Inhibitors. PTC publication no. WO 9321214, October 1993. (c) Veale, C. A.; Steelman, G. B.; Chow, M. M. Efficient Method for the Synthesis of 1,4-Disubstituted 5-Carbomethoxy-pyrimidin-6-ones. J. Org. Chem. 1993, 58, 4490-4493. (d) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 1259-1261.
20. 3. See: (a) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Pyrimidinyl Acetamides as Elastase Inhibitors. European Patent Application, publication no. WO 9321210, October 1993. (b) Bernstein, P. R.; Edwards, P. D.; Shaw, A.; Shenvi, A. B.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Alpha-Aminoboronic Acid Peptides and Their Use as Elastase Inhibitors. PTC publication no. WO 9321214, October 1993. (c) Veale, C. A.; Steelman, G. B.; Chow, M. M. Efficient Method for the Synthesis of 1,4-Disubstituted 5-Carbomethoxy-pyrimidin-6-ones. J. Org. Chem. 1993, 58, 4490-4493. (d) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 1259-1261.
21. For a related pyridone ring system having utility for elastase inhibition, see: (a) Bernstein, P. R.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Lactam Peptides Having HLE Inhibiting Activity. European Patent Application, publication no. WO 9321209, October 1993. (b) Bernstein, P. R.; Andisik, D.; Bradley, P. K.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; Edwards, P. D.; Feeney, S.; Gomes, B. C.; Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Non-Peptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-ray Crystallographic Analysis, and Structure-Activity Relationships For a Series of Orally Active 3-Amino-6-phenylpyridin-2-one Trifluoromethyl Ketones. J. Med. Chem. 1994, 37, 3313-3326 and references therein.
22. For a related pyridone ring system having utility for elastase inhibition, see: (a) Bernstein, P. R.; Shaw, A.; Thomas, R. M.; Veale, C. A.; Warner, P.; Wolanin, D. J. Lactam Peptides Having HLE Inhibiting Activity. European Patent Application, publication no. WO 9321209, October 1993. (b) Bernstein, P. R.; Andisik, D.; Bradley, P. K.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; Edwards, P. D.; Feeney, S.; Gomes, B. C.; Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Non-Peptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-ray Crystallographic Analysis, and Structure-Activity Relationships For a Series of Orally Active 3-Amino-6-phenylpyridin-2-one Trifluoromethyl Ketones. J. Med. Chem. 1994, 37, 3313-3326 and references therein.
23. Amine hydrochlorides 19-21 are stable in solid form to storage at O °C for several months without decomposition.
24. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. New Coupling Reagents in Peptide Chemistry. Tetrahedron Lett. 1989, 30, 1927-1930.
25. All new compounds gave physical and spectroscopic data consistent with their structure.
26. Wommack, J. B.; Pearson, D. E. Potential Antimalarials. IV. Quinoline-α,α-dialkylmethanols. J. Med. Chem. 1970, 13, 383-386.
27. -1) shows these compounds to be essentially equipotent against ICE.