Lead optimization of melanin concentrating hormone receptor 1 antagonists with low hERG channel activity

Current Topics in Medicinal Chemistry

Volumn 8, Issue 13, 2008, Pages 1152-1157

  Judd, Andrew S ^a   Souers, Andrew J ^a   Kym, Philip R ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

hERG channel; MCHr1 antagonist

Indexed keywords

BENZAMIDE DERIVATIVE; COUMARIN; DOFETILIDE; MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; PIPAMPERONE; POTASSIUM CHANNEL HERG;

BINDING AFFINITY; CHEMICAL MODIFICATION; DRUG ACTIVITY; DRUG CROSS REACTIVITY; DRUG DISTRIBUTION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG STRUCTURE; HEART REPOLARIZATION; HEMODYNAMICS; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; OBESITY; PATCH CLAMP; QT PROLONGATION; REVIEW; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; TORSADE DES POINTES; WEIGHT REDUCTION;

ANIMALS; CARDIOVASCULAR SYSTEM; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; PROTEIN BINDING; RECEPTORS, PITUITARY HORMONE;

EID: 52949122881     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802608785700052     Document Type: Review

References (26)

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16. For current statistics on the obesity epidemic, see http:// win.niddk.nih.gov.
17. See also: (a) Souers, A. J.; Wodka, D.; Gao, J.; Lewis, J. C.; Vasudevan, A.; Brodjian, S.; Dayton, B.; Ogiela, C. A.; Fry, D.; Hernandez, L. E.; Marsh, K. C.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3. Biorg. Med. Chem. Lett. 2004, 14(19), 4883-4886.
18. (b) Vasudevan, A.; LaMarche, M.J.; Blackburn, C.; Che, J.L.; Luchaco-Cullis, C.A.; Lai, S.; Marsilje, T.H.; Patane, M.A.; Souers, A.J.; Wodka, D.; Geddes, B.; Chen, S.; Brodjian, S.; Falls, D.H.; Dayton, B.D.; Bush, E.; Brune, M.; Shapiro, R.D.; Marsh, K.C.; Hernandez, L.E.; Sham, H.L.; Collins, C.A.; Kym, P.R. Identification of ortho-amino benzamides and nicotinamides as MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 4174-4179.
19. (c) Souers, A.J.; Iyengar, R.R.; Judd, A.S.; Beno, D.W.A.; Gao, J.; Zhao, G.; Brune, M.E.; Napier, J.J.; Mulhern, M.M.; Lynch, J.K.; Freeman, J.C.; Wodka, D.; Chen, C.J.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Diaz, G. J.; Bush, E.N.; Shapiro, R.; Droz, B.A.; Knourek-Segel, V.; Hernandez, L.E.; Marsh, K.C.; Reilly, R.M.; Sham, H.L.; Collins, C.A.; Kym, P.R. Constrained 7- fluorocarboxychromone-4-aminopiperidine based melanin-concentrating hormone receptor 1 antagonists: The effects of chirality on substituted indan-1-ylamines. Bioorg. Med. Chem. Lett. 2007, 17, 884-889.
20. Kym, P.R.; Judd, A.S.; Lynch, J.K.; Iyengar, R.; Vasudevan, A.; Souers, A.J. Lead optimization strategies and tactics applied to the discovery of melanin concentrating hormone receptor 1 antagonists. Curr. Top. Med. Chem. 2007, 7, 1471-1488.
21. Kym, P. R.; Souers, A. J.; Campbell, T. J.; Lynch, J. K.; Judd, A. S.; Iyengar, R.; Vasudevan, A.; Gao, J.; Freeman, J. C.; Wodka, D.; Mulhern, M.; Zhao, G.; Wagaw, S.; Napier, J. J.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Segreti, J.; Fryer, R. M.; Preusser, L. C.; Reinhart, G. A.; Hernandez, L.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Polakowski, J. S. Screening for cardiovascular safety: A structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists. J. Med. Chem. 2006, 49, 2339-2352.
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24. The correlation between cLogP and hERG affinity has been reviewed: Jamieson, C.; Moir, E.M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: Highlights and hangups. J. Med. Chem. 2006, 49, 5029-5046.
25. Iyengar, R. R.; Lynch, J. K.; Mulhern, M. M.; Judd, A. S.; Freeman, J. C.; Gao, J.; Souers, A. J.; Zhao, G.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Swanson, S.; Su, Z.; Martin, R. L.; Leitza, S. T.; Housman, K. A.; Diaz, G.; Collins, C. A.; Sham, H. L.; Kym, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 874-878.
26. Judd, A.S.; Souers, A.J.; Wodka, D.; Zhao, G.; Mulhern, M.; Iyengar, R.; Gao, J.; Lynch, J.K.; Freeman, J.C.; Falls, H.D.; Brodjian, S.; Dayton, B.; Reilly, R.M.; Gintant, G.; Limberis, J.L.; Mikhail, A.; Leitza, S.; Houseman, K.A.; Diaz, G., Bush, E.N.; Shapiro, R.; Knourek-Segel, V.; Hernandez, L.; Marsh, K.; Sham, H.L.; Collins, C.A.; Kym, P.R. Identification of diamino chromone-2-carboxamides as MCHr1 antagonists with minimal hERG channel activity. Bioorg. Med. Chem. Lett. 2007, 17, 2365-2371.