The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 7, 2012, Pages 2585-2589

  Ho, Ginny D ^a   Michael Seganish, W ^a   Bercovici, Ana ^a   Tulshian, Deen ^a   Greenlee, William J ^a   Van Rijn, Rachel ^a   Hruza, Alan ^a   Xiao, Li ^a   Rindgen, Diane ^a   Mullins, Deborra ^a   Guzzi, Mario ^a   Zhang, Xiaoping ^a   Bleickardt, Carina ^a   Hodgson, Robert ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

PDE10A; Phosphodieasterase inhibitors; Schizophrenia

Indexed keywords

DIHYDROIMIDAZOISOQUINOLINE DERIVATIVE; DIZOCILPINE; NEUROLEPTIC AGENT; PHOSPHODIESTERASE 10A; PHOSPHODIESTERASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; DRUG IDENTIFICATION; HYPERACTIVITY; NONHUMAN; RAT; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION;

ANIMALS; AREA UNDER CURVE; CRYSTALLOGRAPHY, X-RAY; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 3; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 7; DIZOCILPINE MALEATE; HAPLORHINI; HUMANS; HYPERKINESIS; IMIDAZOLES; ISOQUINOLINES; MALE; MODELS, MOLECULAR; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PSYCHOTROPIC DRUGS; RATS; SCHIZOPHRENIA; STRUCTURE-ACTIVITY RELATIONSHIP;

RATTUS;

EID: 84862826287     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.01.113     Document Type: Article

References (12)

1. C.J. Schmidt, D.S. Chapin, J. Cianfrogna, M.L. Corman, M. Hajos, J.F. Harms, W.E. Hoffman, L.A. Lebel, S.A. McCarthy, F.R. Nelson, C. Proulx-LaFrance, M.J. Majchrzak, A.D. Ramirez, K. Schmidt, P.A. Seymour, J.A. Siuciak, F.D. Tingley III, R.D. Williams, P.R. Verhoest, and F.S. Menniti Pharmacol. Exp. Ther. 325 2008 681 and references cited therein
2. J.W. Newcomer CNS Drugs 19 2005 1
3. D.E. Casey Am. J. Med. 118 2005 15S
4. D.M. Taylor Acta Psychiatr. Scand. 107 2003 85
5. Niewoehner, U.; Bauser, M.; Ergueden, J.; Flubacher, D.; Naab, P.; Repp, T.; Stoltefuss, J.; Burkhardt, N.; Sewing, A.; Schauer, M.; Schlemmer, K.; Weber, O.; Boyer, S. J.; Miglarese, M. PCT Int. Appl. WO 2002048144, 2002.
6. Maier, T.; Graedler, U.; Baer, T.; Vennemann, M. PCT Int. Appl. WO 2005002579, 2005.
7. A. Sugiyama, Y. Satoh, and K. Hashimoto J. Cardiovasc. Pharmacol. 38 2001 268
8. A. Van de Water, J. D'Aubioul, W. Van Gerven, D. De Chaffoyde Courcelles, E. Freyne, R. Xhonneux, R.S. Reneman, and P.A. Janssen J. Arch. Int. Pharmacodyn. Ther. 1992 60
9. W.A. Korfmacher, K.A. Cox, K.J. Ng, J. Veals, Y. Hsieh, S. Wainhaus, L. Broske, D. Prelusky, A. Nomeir, and R.E. White Rapid Commun Mass Spectrom. 15 2001 335 The animal was dosed 10 mg/kg orally. The plasma drug exposure was measured from 0 to 6 h, and the brain drug concentration was measured after 6 h. The brain/plasma ratio is the ratio of brain and plasma drug concentration at 6-h
10. R.A. Hodgson, L.A. Hyde, D.H. Guthrie, M.E. Cohen-Williams, P.T. Leach, T.M. Kazdoba, C.J. Bleickardt, S.X. Lu, E.M. Parker, and G.B. Varty Pharmacol., Biochem. Behav. 98 2011 181
11. T.T. Wager, X. Hou, P.R. Verhoest, and A. Villalobos ACS Chem. Neurosci. 1 2010 435 The softwares used to calculate physicochemical properties to obtain the CNS MPO scores are Biobyte (c Log P), ACD/Laboratories (pKa), Pipeline Pilot (PSA) and a hybrid model using Biobyte's c log P and ACD/Laboratories' pKa developed at Schering-Plough (c Log D)
12. C.J. Helal, Z. Kang, X. Hou, J. Pandit, T.A. Chappie, J.M. Humphrey, E.S. Marr, K.F. Fennell, L.K. Chenard, C. Fox, C.J. Schmidt, R.D. Williams, D.S. Chapin, J. Siuciak, L. Lebel, F. Menniti, J. Cianfrogna, K.R. Fonseca, F.R. Nelson, R. O'Connor, M. MacDougall, L. McDowell, and S. Liras J. Med. Chem. 54 2011 4536