Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia

Journal of Medicinal Chemistry

Volumn 54, Issue 13, 2011, Pages 4536-4547

  Helal, Christopher J ^a,b   Kang, Zhijun ^a,b   Hou, Xinjun ^a,b   Pandit, Jayvardhan ^a,b   Chappie, Thomas A ^a,b   Humphrey, John M ^a,b   Marr, Eric S ^a,b   Fennell, Kimberly F ^a,b   Chenard, Lois K ^a,b   Fox, Carol ^a,b   Schmidt, Christopher J ^a,b   Williams, Robert D ^a,b   Chapin, Douglas S ^a,b   Siuciak, Judith ^a,b   Lebel, Lorraine ^a,b   Menniti, Frank ^a,b   Cianfrogna, Julia ^a,b   Fonseca, Kari R ^a,b   Nelson, Frederick R ^a,b   O Connor, Rebecca ^a,b   MacDougall, Mary ^a,b   McDowell, Laura ^a,b   Liras, Spiros ^a,b   more..

^a PFIZER INC   (United States)

^b NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [2 (ISOQUINOLIN 7 YLOXY)ETHYL]QUINOLINE; 4,5 BIS(4 METHOXYPHENYL) 2 (2 THIENYL) 1H IMIDAZOLE; 6 METHOXY 7 (2 QUINOLIN 2 YLETHOXY)QUINAZOLINE; 6 METHOXYQUINAZOLIN 7 OL; 6,7 DIMETHOXY 4 (3 PHENYLPIPERIDIN 1 YL)QUINAZOLINE; 6,7 DIMETHOXYQUINAZOLINE; 7 METHOXY 3 METHYL 6 (2 QUINOLIN 2 YLETHOXY)QUINAZOLIN 4(3H) ONE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (2 PYRIDIN 2 YLETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (2 PYRIDIN 3 YLETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (2 PYRIDIN 4 YLETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (2 QUINOLIN 2 YLETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (PYRIDIN 2 YLMETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (PYRIDIN 3 YLMETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (PYRIDIN 4 YLMETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 (QUINOLIN 2 YLMETHOXY) QUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL) 6 PROPOXYQUINAZOLINE; 7 METHOXY 4 (3 PHENYLPIPERIDIN 1 YL)QUINAZOLIN 6 OL; 7 METHOXY 4 PYRIDIN 3 YL 6 (2 QUINOLIN 2 YLETHOXY)QUINAZOLINE; 7 METHOXY 6 (2 PHENYLETHOXY) 4 (3 PHENYLPIPERIDIN 1 YL)QUINAZOLINE; 7 METHOXY 6 [3 (1 METHYL 1H BENZIMIDAZOL 2 YL)PROPOXY] 4 (3 PHENYLPIPERIDIN 1 YL)QUINAZOLINE; 7 METHOXY N,N DIMETHYL 6 (2 QUINOLIN 2 YLETHOXY)QUINAZOLIN 4 AMINE; BENZIMIDAZOLE DERIVATIVE; GLYCOPROTEIN P; PHOSPHODIESTERASE 10A INHIBITOR; QUINAZOLINE; QUINAZOLINE DERIVATIVE; QUINAZOLINONE DERIVATIVE; TRIARYLIMIDAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING SITE; BLOOD BRAIN BARRIER; CRYSTAL STRUCTURE; DRUG BINDING; DRUG CLEARANCE; DRUG DESIGN; DRUG PENETRATION; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; IN VIVO STUDY; LIVER MICROSOME; NONHUMAN; PHYSICAL CHEMISTRY; RAT; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS;

ANIMALS; ANTIPSYCHOTIC AGENTS; AVOIDANCE LEARNING; BINDING SITES; BLOOD-BRAIN BARRIER; CORPUS STRIATUM; CRYSTALLOGRAPHY, X-RAY; CYCLIC GMP; DATABASES, FACTUAL; DRUG DESIGN; HUMANS; MICE; MICE, KNOCKOUT; MICROSOMES, LIVER; MODELS, MOLECULAR; P-GLYCOPROTEIN; PERMEABILITY; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PROTEIN CONFORMATION; SCHIZOPHRENIA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79960165571     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2001508     Document Type: Article

References (23)

1. Jeon, Y. H.; Heo, Y. S.; Kim, C. M.; Hyun, Y. L.; Lee, T. G.; Ro, S.; Cho, J. M. Phosphodiesterase: Overview of Protein Structures, Potential Therapeutic Applications and Recent Progress in Drug Development Cell. Mol. Life Sci. 2005, 62, 1198-1220 (Pubitemid 40880125)
2. Manallack, D. T.; Hughes, R. A.; Thompson, P. E. The Next Generation of Phosphodiesterase Inhibitors: Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases J. Med. Chem. 2005, 48, 3449-3462 (Pubitemid 40664094)
3. Card, G. L.; England, B. P.; Suzuki, Y.; Fong, D.; Powell, B.; Lee, B.; Luu, C.; Tabrizizad, M.; Gillette, S.; Ibrahim, P. N.; Artis, D. R.; Bollag, G.; Milburn, M. V.; Kim, S.-H.; Schlessinger, J.; Zhang, K. Y. J. Structural Basis for the Activity of Drugs That Inhibit Phosphodiesterases Structure (Cambridge, MA, U. S. A.) 2004, 12, 2233-2247 (Pubitemid 39593200)
4. Chappie, T. A.; Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox, C. B.; Lebel, L. A.; Liras, S.; Marr, E. S.; Menniti, F. S.; Pandit, J.; Schmidt, C. J.; Tu, M.; Williams, R. D.; Yang, F. V. Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors J. Med. Chem. 2007, 50, 182-185 (Pubitemid 46147698)
5. Verhoest, P. R.; Chapin, D. S.; Corman, M.; Fonseca, K.; Harms, J. F.; Hou, X.; Marr, E. S.; Menniti, F. S.; Nelson, F.; O'Connor, R.; Pandit, J.; Proulx-LaFrance, C.; Schmidt, A. W.; Schmidt, C. J.; Suiciak, J. A.; Liras, S. Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1 H -pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920)(I) for the Treatment of Schizophrenia J. Med. Chem. 2009, 52, 5188-5196
6. Hoefgen, N.; Stange, H.; Schindler, R.; Lankau, H.-J.; Grunwald, C.; Langen, B.; Egerland, U.; Tremmel, P.; Pangalos, M. N.; Marquis, K. L.; Hage, T.; Harrison, B. L.; Malamas, M. S.; Brandon, N. J.; Kronbach, T. Discovery of Imidazo[1,5- a ]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitors J. Med. Chem. 2010, 53, 4399-4411
7. Seeger, T. F.; Bartlett, B.; Coskran, T. M.; Culp, J. S.; James, L. C.; Krull, D. L.; Lanfear, J.; Ryan, A. M.; Schmidt, C. J.; Strick, C. A.; Varghese, A. H.; Williams, R. D.; Wylie, P. G.; Menniti, F. S. Immunohistochemical Localization of PDE10A in the Rat Brain Brain Res. 2003, 985, 113-126 (Pubitemid 37088176)
8. Schmidt, C. J.; Chapin, D. S.; Cianfrogna, J.; Corman, M. L.; Hajos, M.; Harms, J. F.; Hoffman, W. E.; Lebel, L. A.; McCarthy, S. A.; Nelson, F. R.; Proulx-LaFrance, C.; Majchrzak, M. J.; Ramirez, A. D.; Schmidt, K.; Seymour, P. A.; Siuciak, J. A.; Tingley, F. D., III; Williams, R. D.; Verhoest, P. R.; Menniti, F. S. Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia J. Pharmacol. Exp. Ther. 2008, 325, 681-690 (Pubitemid 351574819)
9. Siuciak, J. A.; Chapin, D. S.; Harms, J. F.; Lebel, L. A.; McCarthy, S. A.; Chambers, L.; Shrikhande, A.; Wong, S.; Menniti, F. S.; Schmidt, C. J. Inhibition of the Striatum-Enriched Phosphodiesterase PDE10A: A Novel Approach to the Treatment of Psychosis Neuropharmacology 2006, 51, 386-396 (Pubitemid 44061894)
10. Strick, C. A.; Schmidt, C. J.; Menniti, F. S. PDE10A: A Striatum-Enriched, Dual-Substrate Phosphodiesterase Cyclic Nucleotide Phosphodiesterases Health Dis. 2007, 237-254
11. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. In vitro P-glycoprotein Assays to Predict the In Vivo Interactions of P-Glycoprotein with Drugs in the Central Nervous System Drug Metab. Dispos. 2008, 36, 268-275 (Pubitemid 351185738)
12. Sugiyama, A.; Satoh, Y.; Hashimoto, K. Electropharmacologic Effects of A New Phosphodiesterase III Inhibitor, Toborinone (OPC-18790), Assessed in An In Vivo Canine Model J. Cardiovasc. Pharmacol. 2001, 38, 268-277 (Pubitemid 32667154)
13. Van de Water, A.; D'Aubioul, J.; Van Gerven, W.; De Chaffoy de Courcelles, D.; Freyne, E.; Xhonneux, R.; Reneman, R. S.; Janssen, P. A. J. Cardiac and Hemodynamic Effects of Intravenous R 80122, A New Phosphodiesterase III Inhibitor, In Anesthetized and Awake Dogs Arch. Int. Pharmacodyn. Ther. 1992, 316, 60-74
14. Pandit, J. Crystal Structure of 3′,5′-Cyclicnucleotide Phosphodiesterase (PDE10A) and Uses Thereof. U.S. Pat. Appl. Publ. 0202550, 2005.
15. Gleeson, M. P. Generation of a Set of Simple, Interpretable ADMET Rules of Thumb J. Med. Chem. 2008, 51, 817-834 (Pubitemid 351304691)
16. Clark, D. E. Rapid Calculation of Polar Molecular Surface Area and Its Application to the Prediction of Transport Phenomena. 2. Prediction of Blood-Brain Barrier Penetration J. Pharm. Sci. 1999, 88, 815-821 (Pubitemid 29398551)
17. Doan, K. M. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs J. Pharmacol. Exp. Ther. 2002, 303, 1029-1037 (Pubitemid 35424386)
18. Gehlhaar, D. K.; Verkhivker, G. M.; Rejto, P. A.; Sherman, C. J.; Fogel, D. B.; Fogel, L. J.; Freer, S. T. Molecular Recognition of the Inhibitor AG-1343 by HIV-1 Protease: Conformationally Flexible Docking by Evolutionary Programming Chem. Biol. 1995, 2, 317-324
19. Marrone, T. J.; Luty, B. A.; Rose, P. W. Discovering High-Affinity Ligands from the Computationally Predicted Structures and Affinities of Small Molecules Bound to A Target: A Virtual Screening Approach Perspect. Drug Discovery Des. 2000, 20, 209-230
20. If all reagents were mixed together at the same time, products from the addition of 5 to the azodicarboxylate were observed with little product. See: Hughes, D. L. The Mitsunobu Reaction Org. React. (Hoboken, NJ, U. S. A.) 1992, 42
21. Helal, C. J. Heteroaromatic Quinoline Compounds as Phosphodiesterase Inhibitors, Their Preparation, Pharmaceutical Compositions, and Use in Treating CNS and Other Disorders.WO 2008/020302 A2, 2008.
22. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand Efficiency: A Useful Metric for Lead Selection Drug Discovery Today 2004, 9, 430-431 (Pubitemid 38510559)
23. Lombardino, J. G. Pharmaceutical Imidazoles. Ger. Offen. DE 2155558, 1972.