De novo design of a picomolar nonbasic 5-HT1B receptor antagonist

Journal of Medicinal Chemistry

Volumn 53, Issue 4, 2010, Pages 1876-1880

  Nugiel, David A ^a   Krumrine, Jennifer R ^a   Hill, Daniel C ^a   Damewood Jr , James R ^a   Bernstein, Peter R ^a   Sobotka Briner, Cynthia D ^a   Liu, Jianwei ^a   Zacco, Anna ^a   Pierson, M Edward ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 BROMO 5 METHYLPHENYLAMINO)BUT 2 ENEDIOIC ACID; 6 FLUORO 4 HYDROXY 8 (1,3,5 TRIMETHYL 1H PYRAZOL 4 YL)CHROMAN 2 CARBOXYLIC ACID; 6 FLUORO 8 (1,3,5 TRIMETHYL 1H PYRAZOL 4 YL)CHROMAN 2 CARBOXYLIC ACID; 6 FLUORO N (6 (4 METHOXYTETRAHYDRO 2H PYRAN 4 YL)PYRIDIN 3 YL) 4 OXO 8 (1,3,5 TRIMETHYL 1H)PYRAZOL 4 YL) 4H CHROMENE 2 CARBOXAMIDE; 6 FLUORO N (6 (4 METHOXYTETRAHYDRO 2H PYRAN 4 YL)PYRIDIN 3 YL) 8 (1,3,5 TRIMETHYL 1H PYRAZOL 4 YL)CHROMAN 2 CARBOXAMIDE; 8 BROMO 5 METHYL 4 OXO 1,4 DIHYDROQUINOLINE 2 CARBOXYLIC ACID; 8 BROMO 5 METHYL 4 OXO 1,4 DIHYDROQUINOLINE 2 CARBOXYLIC ACID (4 MORPHOLIN 4 YLPHENYL)AMIDE; PIPERAZINE; POTASSIUM 6 FLUORO 4 OXO 8 (1,3,5 TRIMETHYL 1H PYRAZOL 4 YL) 4H CHROMENE 2 CARBOXYLATE; PYRAZOLE; SEROTONIN 1B ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG METABOLISM; DRUG STRUCTURE; DRUG SYNTHESIS; GUINEA PIG; HYPOTHERMIA; IN VITRO STUDY; LIPIDOSIS; NONHUMAN;

ANIMALS; BINDING, COMPETITIVE; CHO CELLS; COMBINATORIAL CHEMISTRY TECHNIQUES; CRICETINAE; CRICETULUS; DRUG DESIGN; DRUG PARTIAL AGONISM; ETHER-A-GO-GO POTASSIUM CHANNELS; GUINEA PIGS; HUMANS; HYPOTHERMIA; LIPIDOSES; PHOSPHOLIPIDS; PIPERAZINES; PYRAZOLES; RADIOLIGAND ASSAY; RECEPTOR, SEROTONIN, 5-HT1B; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77649223492     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901200t     Document Type: Article

References (26)

1. Hoyer, D.; Harmon, J. P.; Martin, G. R. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol., Biochem. Behay. 2002, 71, 533-554. (Pubitemid 34219205)
2. 1D receptor subtypes. Trends Pharmacol. Sci. 1996, 17, 103-105.
3. 1B/1D receptor antagonists and agonists and their potential, therapeutic applications. Curr. Top. Med. Chem. 2002, 2, 559-574.
4. Helal, C. J. Potent and Selective 5-HT1B/D Antagonists/Inverse Agonists with Reduced hERG Affinity for the Treatment of Depression. Presented, at the 235th National Meeting of the American Chemical Society, New Orleans, LA, Apr 6-10, 2008; MEDI-154.
5. Trumpp-Kallmeyer, S.; Hoklack, J.; Bruinvels, A.; Hibert, M. Three-dimensional models of neurotransmitter G-binding protein coupled, receptors. Mol. Pharmacol. 1991, 40, 8-15.
6. Hancox, J. C.; McPate, M. J.; Harchi, A. E.; Zhang, Y. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol. Ther. 2008, 119, 118-132.
7. Redfern, W. S.; Carlsson, L.; Davis, A. S.; Lynch, W. G.; MacKenzie, I.; Palethorpe, S.; Siegl, P. K.; Strang, I.; Sullivan, A. T.; Wallis, R.; Camm, A. J.; Hammond, T. G. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 2003, 58, 32-45.
8. Reasor, M. J.; Hatings, K. L.; Ulrich, R. G. Drug-induced phospholipids: issues and future directions. Expert Opin. Drug Saf. 2006, 5, 567-583.
9. 1B antagonists. Bioorg. Med. Chem. 2007, 15, 939-950.
10. Bernstein, P.; Hill, D.; Nugiel, D.; Pierson, E.; Shenvi, A.; Jacobs, R. Chroman Compounds as 5-HT1B Receptor Antagonists, Their Preparation, Pharmaceutical Compositions, and Use in Therapy. PCT Int. Appl. WO 2007053095, 2007.
11. Information on this chroman was presented, previously: Bernstein, P. R. Challenge of CNS Drug Discovery. Presented at the 235th National Meeting of the American Chemical Society, New Orleans. LA, Apr 6-10, 2008; MEDI-143.
12. 1B ligands is in preparation.
13. Damewood, J. R.; Lerman, C. L. Flexible Ligand Alignment Protocols and Their Use in de Novo Design. Presented at the 234th National Meeting of the American Chemical Society, Boston, MA, Aug 19-23, 2007; CINF-34. NovoFLAP is a proprietary computer-aided de novo tool that uses an evolutionary algorithm (EA-Inventor is available from Tripos International, 1699 South Hanley Rd, St. Louis, MO 63144) and a scoring function based on shape and pharmacophore features.
14. Sawyer, J. S.; Beight, D. W.; Britt, K. S.; Anderson, B. D.; Campbell. R. M.; Goodson, T.; Herron, D. K.; Li, H. Y.; McMillen, W. T.; Mort, N.; Parsons, S.; Smith, E. C.; Wagner, J. R.; Yan, L.; Zhang, F.; Yingling, J. M. Synthesis and activity of new aryland heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[l ,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg. Med. Chem. Med. Lett. 2004, 14, 3581-3584.
15. Suzuki, A. Synthetic studies via the cross-coupling reaction of organoboron derivatives with organic halides. Pure Appl. Chem. 1991, 63,419-422.
16. Robinson, G. E.; Cunningham, O. R.; Dekhane, M.; McManus, J. C.; O'Kearney-McMullan, A.; Mirajkar, A. M.; Mishra, V.; Norton, A. K.; Venugopalan, B.; Williams, E. G. Successful development and scale-up of a palladium-catalyzed animation process in the manufacture of ZM549865. Org. Process Res. Dev. 2004, 8 (6), 925-930.
17. For references and instrument applications, see www.thalesnano.com.
18. This compound was resolved by chiral chromatography. Both enantiomers are partial agonists.
19. Moderate human, cLint (60 (μL/min)/mg) and an efflux ratio of 5.9 (B:A/A:B ratio in MDR1 transfected cells is described in the following: Hochman, J. H.; Pudvah, N.; Qiu, J.; Yamazaki, M.; Tang, C.; Lin, J.; Prueksaritanont, T. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm. Res. 2004, 21, 1686-1691.
20. Unpublished results. A variety of receptors that might have interfered, with the in vivo experiments were specifically targeted. For binding assay information and values for standard reference compounds, see http://discovery.mdsps.com/Catalog/.
21. 1D receptors mediate SKF 99l0lH-induced hypothermia in the guinea pig. J. Psycho-Pharmacol. 1995, 9, 234-241.
22. 1B receptors causes hypothermia in the guinea pig. Eur. J. Pharmacol. 1997, 331,169-174.
23. Bridgland-Taylor, M. H.; Hargreaves, A. C.; Easter, A.; Orme, A.; Henthorn, D. C.; Ding, M.; Davis, A. M.; Small, B. G.; Heapy, C. G.; Abi-Gerges, N.; Persson, F.; Jacobson, L; Sullivan, M.; Albertson, N.; Hammond, T. G.; Sullivan, E.; Valentin, J.-P.; Pollard, C. E. Optimisation, and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT. J. Pharmacol Toxicol. 2006, 54, 189-199.
24. Morelli, J. K.; Buehrle, M.; Pognan, F.; Barone, L. R.; Fieles, W.; Ciaccio, P. J. Validation of an in vitro screen for phospholipidosis using a high-content biology platform. Cell. Biol. Toxicol. 2006, 22, 15-27.
25. In vivo pharmacology: Hudzik, T.; Smolka, J; Litwin, L.; Porrey, T.; Pierson, E. In vivo pharmacology of AZD1134, a novel 5-HT1B antagonist. Eur. Neuropsychopharmacol. 2003, 13 (Suppl. 4), S181-S182.
26. Process Chemistry (as M549865): Robinson, G. E.; Cunningham, O. R.; Dekhane, M.; McManus, J. C.; O'Keamey-McMullan, A.; Mirajkar, A. M.; Vikas Mishra; Norton, A. K.; Venugopalan, B.; Williams, E. G. Successful development and scale-up of a palladiumcatalysed animation process in the manufacture of ZM549865. Org. Process Res. Dev. 2004, 8, 925-930. Development status: http://integrity.prous.com, entry no.323892.