Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists

Journal of Medicinal Chemistry

Volumn 57, Issue 14, 2014, Pages 6128-6140

  McCoull, William ^a   Barton, Peter ^a   Brown, Alastair J H ^a   Bowker, Suzanne S ^a   Cameron, Jennifer ^a   Clarke, David S ^a   Davies, Robert D M ^a   Dossetter, Alexander G ^a   Ertan, Anne ^a   Fenwick, Mark ^a   Green, Clive ^a   Holmes, Jane L ^a   Martin, Nathaniel ^a   Masters, David ^a   Moore, Jane E ^a   Newcombe, Nicholas J ^a   Newton, Claire ^a   Pointon, Helen ^a   Robb, Graeme R ^a   Sheldon, Christopher ^a   Stokes, Stephen ^a   Morgan, David ^a   more..

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 CHLORO 5 MORPHOLIN 4 YL BENZAMIDE; 2 CHLORO N (6 (1 METHYLPIPERIDIN 4 YLSULFONYL)BENZOTHIAZOL 2 YLCARBAMOYL) 5 MORPHOLINOBENZAMIDE; 2 CHLORO N (6 (3 IODOPROPYLSULFONYL)BENZO[D]THIAZOL 2 YLCARBAMOYL)BENZAMIDE; 6 (3 CHLOROPROPYLSULFANYL)BENZOTHIAZOL 2 AMINE; 6 (3 CHLOROPROPYLSULFONYL)BENZOTHIAZOL 2 AMINE; 6 (3 IODOPROPYLSULFONYL)BENZOTHIAZOL 2 AMINE; ANTIOBESITY AGENT; BENZOTHIAZOLE; GHRELIN RECEPTOR; GHS R1A INVERSE AGONIST; HORMONE RECEPTOR STIMULATING AGENT; N (6 (3 (4 METHYLPIPERAZIN 1 YL)PROPYLSULFONYL)BENZO[D]THIAZOL 2 YLCARBONYL) 5 MORPHOLINOBENZAMIDE; PIPERAZINE DERIVATIVE; TERT BUTYL 4 (2 AMINOBENZOTHIAZOL 6 YLSULFONYL)PIPERIDINE 1 CARBOXYLATE; TERT BUTYL 4 (2 AMINOBENZOTHIAZOL 6 YLTHIO)PIPERIDINE 1 CARBOXYLATE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CENTRAL NERVOUS SYSTEM; DRUG CLEARANCE; DRUG SOLUBILITY; DRUG STRUCTURE; FOOD INTAKE; HIGH THROUGHPUT SCREENING; INVERSE AGONISM; LIPOPHILICITY; MOUSE; NONHUMAN; PARTIAL AGONISM; PLASMA PROTEIN BINDING; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INVERSE AGONISM; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; RECEPTORS, GHRELIN; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 84905041580     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500610n     Document Type: Article

References (46)

1. Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature 1999, 402, 656-660
2. Kojima, M.; Hosoda, H.; Matsuo, H.; Kangawa, K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor Trends Endocrinol. Metab. 2001, 12, 118-122
3. Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Seeley, R. J.; Baskin, D. G. Central nervous system control of food intake Nature 2000, 404, 661-671
4. Cummings, D. E.; Purnell, J. Q.; Frayo, R. S.; Schmidova, K.; Wisse, B. E.; Weigle, D. S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans Diabetes 2001, 50, 1714-1719
5. Wren, A. M.; Seal, L. J.; Cohen, M. A.; Brynes, A. E.; Frost, G. S.; Murphy, K. G.; Dhillo, W. S.; Ghatei, M. A.; Bloom, S. R. Ghrelin enhances appetite and increases food intake in humans J. Clin. Endocrinol. Metab. 2001, 86, 5992-5992
6. Alvarez-Castro, P.; Pena, L.; Cordido, F. Ghrelin in obesity, physiological and pharmacological considerations Mini-Rev. Med. Chem. 2013, 13, 541-552
7. Depoortere, I. Targeting the ghrelin receptor to regulate food intake Regul. Pept. 2009, 156, 13-23
8. Carpino, P. A.; Ho, G. Modulators of the ghrelin system as potential treatments for obesity and diabetes Expert Opin. Ther. Pat. 2008, 18, 1253-1263
9. Soares, J.; Roncon-Albuquerque, R., Jr; Leite-Moreira, A. Ghrelin and ghrelin receptor inhibitors: agents in the treatment of obesity Expert Opin. Ther. Targets 2008, 12, 1177-1189
10. Zhao, H.; Liu, G. Growth hormone secretagogue receptor antagonists as anti-obesity therapies? Still an open question Curr. Opin. Drug Discovery Dev. 2006, 9, 509-515
11. Chollet, C.; Meyer, K.; Beck-Sickinger, A. G. Ghrelin-a novel generation of anti-obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues J. Pept. Sci. 2009, 15, 711-730
12. Ahima, R. S. Antagonism of ghrelin for glycemic control in type 2 diabetes mellitus? Endocrinology 2007, 148, 5173-5174
13. Damian, M.; Marie, J.; Leyris, J.; Fehrentz, J.; Verdie, P.; Martinez, J.; Baneres, J.; Mary, S. High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs J. Biol. Chem. 2012, 287, 3630-3641
14. Holst, B.; Cygankiewicz, A.; Jensen, T. H.; Ankersen, M.; Schwartz, T. W. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist Mol. Endocrinol. 2003, 17, 2201-2210
15. Mokrosinski, J.; Frimurer, T. M.; Sivertsen, B.; Schwartz, T. W.; Holst, B. Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop J. Biol. Chem. 2012, 287, 33488-33502
16. Holst, B.; Schwartz, T. W. Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation Trends Pharmacol. Sci. 2004, 25, 113-117
17. Rudolph, J.; Esler, W. P.; O'Connor, S.; Coish, P. D. G.; Wickens, P. L.; Brands, M.; Bierer, D. E.; Bloomquist, B. T.; Bondar, G.; Chen, L.; Chuang, C.; Claus, T. H.; Fathi, Z.; Fu, W.; Khire, U. R.; Kristie, J. A.; Liu, X.; Lowe, D. B.; McClure, A. C.; Michels, M.; Ortiz, A. A.; Ramsden, P. D.; Schoenleber, R. W.; Shelekhin, T. E.; Vakalopoulos, A.; Tang, W.; Wang, L.; Yi, L.; Gardell, S. J.; Livingston, J. N.; Sweet, L. J.; Bullock, W. H. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity J. Med. Chem. 2007, 50, 5202-5216
18. Esler, W. P.; Rudolph, J.; Claus, T. H.; Tang, W.; Barucci, N.; Brown, S.; Bullock, W.; Daly, M.; DeCarr, L.; Li, Y.; Milardo, L.; Molstad, D.; Zhu, J.; Gardell, S. J.; Livingston, J. N.; Sweet, L. J. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss Endocrinology 2007, 148, 5175-5185
19. Mihalic, J. T.; Kim, Y.; Lizarzaburu, M.; Chen, X.; Deignan, J.; Wanska, M.; Yu, M.; Fu, J.; Chen, X.; Zhang, A.; Connors, R.; Liang, L.; Lindstrom, M.; Ma, J.; Tang, L.; Dai, K.; Li, L. Discovery of a new class of ghrelin receptor antagonists Bioorg. Med. Chem. Lett. 2012, 22, 2046-2051
20. Puleo, L.; Marini, P.; Avallone, R.; Zanchet, M.; Bandiera, S.; Baroni, M.; Croci, T. Synthesis and pharmacological evaluation of indolinone derivatives as novel ghrelin receptor antagonists Bioorg. Med. Chem. 2012, 20, 5623-5636
21. Hanrahan, P.; Bell, J.; Bottomley, G.; Bradley, S.; Clarke, P.; Curtis, E.; Davis, S.; Dawson, G.; Horswill, J.; Keily, J.; Moore, G.; Rasamison, C.; Bloxham, J. Substituted azaquinazolinones as modulators of GHSr-1a for the treatment of type II diabetes and obesity Bioorg. Med. Chem. Lett. 2012, 22, 2271-2278
22. Sabbatini, F. M.; Melotto, S.; Bernasconi, G.; Bromidge, S. M.; D'Adamo, L.; Rinaldi, M.; Savoia, C.; Mundi, C.; Di Francesco, C.; Zonzini, L.; Costantini, V. J. A.; Perini, B.; Valerio, E.; Pozzan, A.; Perdonà, E.; Visentini, F.; Corsi, M.; Di Fabio, R. Azabicyclo[3.1.0]hexane-1-carbohydrazides as potent and selective GHSR1a ligands presenting a specific in vivo behavior ChemMedChem 2011, 6, 1981-1985
23. Serby, M. D.; Zhao, H.; Szczepankiewicz, B. G.; Kosogof, C.; Xin, Z.; Liu, B.; Liu, M.; Nelson, L. T. J.; Kaszubska, W.; Falls, H. D.; Schaefer, V.; Bush, E. N.; Shapiro, R.; Droz, B. A.; Knourek-Segel, V. E.; Fey, T. A.; Brune, M. E.; Beno, D. W. A.; Turner, T. M.; Collins, C. A.; Jacobson, P. B.; Sham, H. L.; Liu, G. 2,4-Diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists J. Med. Chem. 2006, 49, 2568-2578
24. Moulin, A.; Brunel, L.; Boeglin, D.; Demange, L.; Ryan, J.; M'Kadmi, C.; Denoyelle, S.; Martinez, J.; Fehrentz, J. The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist Amino Acids 2013, 44, 301-314
25. Holst, B.; Lang, M.; Brandt, E.; Bach, A.; Howard, A.; Frimurer, T. M.; Beck-Sickinger, A.; Schwartz, T. W. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor Mol. Pharmacol. 2006, 70, 936-946
26. Pasternak, A.; Goble, S. D.; deJesus, R. K.; Hreniuk, D. L.; Chung, C. C.; Tota, M. R.; Mazur, P.; Feighner, S. D.; Howard, A. D.; Mills, S. G.; Yang, L. Discovery and optimization of novel 4-[(aminocarbonyl)amino]- N -[4-(2-aminoethyl)phenyl]benzenesulfonamide ghrelin receptor antagonists Bioorg. Med. Chem. Lett. 2009, 19, 6237-6240
27. Kung, D. W.; Coffey, S. B.; Jones, R. M.; Cabral, S.; Jiao, W.; Fichtner, M.; Carpino, P. A.; Rose, C. R.; Hank, R. F.; Lopaze, M. G.; Swartz, R.; Chen, H.; Hendsch, Z.; Posner, B.; Wielis, C. F.; Manning, B.; Dubins, J.; Stock, I. A.; Varma, S.; Campbell, M.; DeBartola, D.; Kosa-Maines, R.; Steyn, S. J.; McClure, K. F. Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor Bioorg. Med. Chem. Lett. 2012, 22, 4281-4287
28. McCoull, W.; Barton, P.; Broo, A.; Brown, A. J. H.; Clarke, D. S.; Coope, G.; Davies, R. D. M.; Dossetter, A. G.; Kelly, E. E.; Knerr, L.; MacFaul, P.; Holmes, J. L.; Martin, N.; Moore, J. E.; Morgan, D.; Newton, C.; Osterlund, K.; Robb, G. R.; Rosevere, E.; Selmi, N.; Stokes, S.; Svensson, T. S.; Ullah, V. B. K.; Williams, E. J. Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity Med. Chem. Commun. 2013, 4, 456-462
29. McClure, K. F.; Jackson, M.; Cameron, K. O.; Kung, D. W.; Perry, D. A.; Orr, S. T. M.; Zhang, Y.; Kohrt, J.; Tu, M.; Gao, H.; Fernando, D.; Jones, R.; Erasga, N.; Wang, G.; Polivkova, J.; Jiao, W.; Swartz, R.; Ueno, H.; Bhattacharya, S. K.; Stock, I. A.; Varma, S.; Bagdasarian, V.; Perez, S.; Kelly-Sullivan, D.; Wang, R.; Kong, J.; Cornelius, P.; Michael, L.; Lee, E.; Janssen, A.; Steyn, S. J.; Lapham, K.; Goosen, T. Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor Bioorg. Med. Chem. Lett. 2013, 23, 5410-5414
30. Bhattacharya, S. K.; Andrews, K.; Beveridge, R.; Cameron, K. O.; Chen, C.; Dunn, M.; Fernando, D.; Gao, H.; Hepworth, D.; Jackson, V. M.; Khot, V.; Kong, J.; Kosa, R. E.; Lapham, K.; Loria, P. M.; Londregan, A. T.; McClure, K. F.; Orr, S. T. M.; Patel, J.; Rose, C.; Saenz, J.; Stock, I. A.; Storer, G.; VanVolkenburg, M.; Vrieze, D.; Wang, G.; Xiao, J.; Zhang, Y. Discovery of PF-5190457, a potent, selective, and orally bioavailable ghrelin receptor inverse agonist clinical candidate ACS Med. Chem. Lett. 2014, 5, 474-479
31. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890
32. Hanson, B. J.; Wetter, J.; Bercher, M. R.; Kopp, L.; Fuerstenau-Sharp, M.; Vedvik, K. L.; Zielinski, T.; Doucette, C.; Whitney, P. J.; Revankar, C. A homogeneous fluorescent live-cell assay for measuring 7-transmembrane receptor activity and agonist functional selectivity through beta-arrestin recruitment J. Biomol. Screening 2009, 14, 798-810
33. Di, L.; Rong, H.; Feng, B. Demystifying brain penetration in central nervous system drug discovery J. Med. Chem. 2013, 56, 2-12
34. Els, S.; Schild, E.; Petersen, P. S.; Kilian, T.; Mokrosinski, J.; Frimurer, T. M.; Chollet, C.; Schwartz, T. W.; Holst, B.; Beck-Sickinger, A. G. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor J. Med. Chem. 2012, 55, 7437-7449
35. Friden, M.; Ducrozet, F.; Middleton, B.; Antonsson, M.; Bredberg, U.; Hammarlund-Udenaes, M. Development of a high-throughput brain slice method for studying drug distribution in the central nervous system Drug Metab. Dispos. 2009, 37, 1226-1233
36. PSA was calculated using in-house software according to a published methodology: Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717
37. Pajouhesh, H.; Lenz, G. Medicinal chemical properties of successful central nervous system drugs NeuroRX 2005, 2, 541-553
38. Rasmussen, S. G. F.; Choi, H.; Fung, J. J.; Pardon, E.; Casarosa, P.; Chae, P. S.; DeVree, B. T.; Rosenbaum, D. M.; Thian, F. S.; Kobilka, T. S.; Schnapp, A.; Konetzki, I.; Sunahara, R. K.; Gellman, S. H.; Pautsch, A.; Steyaert, J.; Weis, W. I.; Kobilka, B. K. Structure of a nanobody-stabilized active state of the β2 adrenoceptor Nature 2011, 469, 175-180
39. Stokes, S.; Martin, N. G. A simple and efficient synthesis of N -benzoyl ureas Tetrahedron Lett. 2012, 53, 4802-4804
40. Bowes, J.; Brown, A. J.; Hamon, J.; Jarolimek, W.; Sridhar, A.; Waldron, G.; Whitebread, S. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling Nat. Rev. Drug Discovery 2012, 11, 909-922
41. Northrup, A. B.; Katcher, M. H.; Altman, M. D.; Chenard, M.; Daniels, M. H.; Deshmukh, S. V.; Falcone, D.; Guerin, D. J.; Hatch, H.; Li, C.; Lu, W.; Lutterbach, B.; Allison, T. J.; Patel, S. B.; Reilly, J. F.; Reutershan, M.; Rickert, K. W.; Rosenstein, C.; Soisson, S. M.; Szewczak, A. A.; Walker, D.; Wilson, K.; Young, J. R.; Pan, B.; Dinsmore, C. J. Discovery of 1-[3-(1-methyl-1 H -pyrazol-4-yl)-5-oxo-5 H -benzo[4,5]cyclohepta[1,2- b ]pyridin-7-yl]- N -(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met J. Med. Chem. 2013, 56, 2294-2310
42. White, J. F.; Noinaj, N.; Shibata, Y.; Love, J.; Kloss, B.; Xu, F.; Gvozdenovic-Jeremic, J.; Shah, P.; Shiloach, J.; Tate, C. G.; Grisshammer, R. Structure of the agonist-bound neurotensin receptor Nature 2012, 490, 508-513
43. Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human κ-opioid receptor in complex with JDTic Nature 2012, 485, 327-332
44. Gayen, A.; Goswami, S. K.; Mukhopadhyay, C. NMR evidence of GM1-induced conformational change of substance P using isotropic bicelles Biochim. Biophys. Acta, Biomembr. 2011, 1808, 127-139
45. Bissantz, C.; Logean, A.; Rognan, D. High-throughput modeling of human G-protein coupled receptors: Amino acid sequence alignment, three-dimensional model building, and receptor library screening J. Chem. Inf. Comput. Sci. 2004, 44, 1162-1176
46. Egecioglu, E.; Jerlhag, E.; Salome, N.; Skibicka, K. P.; Haage, D.; Bohlooly-Y, M.; Andersson, D.; Bjursell, M.; Perrissoud, D.; Engel, J. A.; Dickson, S. L. Ghrelin increases intake of rewarding food in rodents Addict. Biol. 2010, 15, 304-311