Discovery of novel and potent orally active calcium-sensing receptor antagonists that stimulate pulselike parathyroid hormone secretion: Synthesis and structure-activity relationships of tetrahydropyrazolopyrimidine derivatives

Journal of Medicinal Chemistry

Volumn 54, Issue 5, 2011, Pages 1430-1440

  Yoshida, Masato ^a   Mori, Akira ^a   Kotani, Etsuo ^a   Oka, Masahiro ^a   Makino, Haruhiko ^a   Fujita, Hisashi ^a   Ban, Junko ^a   Ikeda, Yukihiro ^a   Kawamoto, Tomohiro ^a   Goto, Mika ^a   Kimura, Hiroyuki ^a   Baba, Atsuo ^a   Yasuma, Tsuneo ^a  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

4 [1 [[(7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 YL)CARBONYL]AMINO] 1 ETHYLPROPYL]BENZYL ACETATE; 4 [1 [[(7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 YL)CARBONYL]AMINO] 1 ETHYLPROPYL]PHENYL ACETATE; 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXYLIC ACID; 7,7 DIMETHYL 5 PHENYL N [1 PROPYL 1 [4 (TRIFLUOROMETHYL)PHENYL]BUTYL] 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; 7,7 DIMETHYL N [1 METHYL 1 [4 (TRIFLUOROMETHYL)PHENYL]ETHYL] 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; ANABOLIC AGENT; CALCIUM SENSING RECEPTOR ANTAGONIST; ETHYL 4 [1 [[(7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 YL)CARBONYL]AMINO] 1 ETHYLPROPYL]BENZOATE; ETHYL 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXYLIC ACID; N (1 ETHYL 1 PHENYLPROPYL) 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 (3 CHLOROPHENYL) 1 ETHYLPROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 (4 CHLOROPHENYL) 1 ETHYLPROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 [4 (BENZYLOXY)PHENYL] 1 ETHYLPROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 BUTYL 1 [4 (TRIFLUOROMETHYL)PHENYL]PENTYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (2 FLUOROPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (3 FLUOROPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (4 FLUOROPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (4 HYDROXYPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (4 IODOPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (4 METHOXYPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 (4 METHYLPHENYL)PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 [4 (2 OXOBUTOXY)PHENYL]PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 [4 (HYDROXYMETHYL)PHENYL]PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ETHYL 1 [4 (TRIFLUOROMETHYL)PHENYL]PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [1 ISOPROPYL 2 METHYL 1 [4 (TRIFLUOROMETHYL)PHENYL]PROPYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; N [DICYCLOHEXYL[4 (TRIFLUOROMETHYL)PHENYL]METHYL] 7,7 DIMETHYL 5 PHENYL 4,5,6,7 TETRAHYDROPYRAZOLO[1,5 A]PYRIMIDINE 3 CARBOXAMIDE; PARATHYROID HORMONE; TETRAHYDROPYRAZOLOPYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; IN VIVO STUDY; LIPOPHILICITY; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NONHUMAN; OSTEOPENIA; PARATHYROID HORMONE RELEASE; RAT; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ADMINISTRATION, ORAL; ANIMALS; BONE DENSITY; BONE DENSITY CONSERVATION AGENTS; BONE DISEASES, METABOLIC; CACO-2 CELLS; CELL MEMBRANE PERMEABILITY; CHO CELLS; CRICETINAE; CRICETULUS; CRYSTALLOGRAPHY, X-RAY; HUMANS; MOLECULAR STRUCTURE; OSTEOCALCIN; OVARIECTOMY; PARATHYROID HORMONE; PYRAZOLES; PYRIMIDINES; RATS; RECEPTORS, CALCIUM-SENSING; SOLUBILITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79952264113     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101452x     Document Type: Article

References (20)

1. Ettinger, M. P. Aging bone and osteoporosis: strategies for preventing fractures in the elderly Arch. Intern. Med. 2003, 163, 2237-2246 (Pubitemid 37248789)
2. Tarantino, U.; Cannata, G.; Lecce, D.; Celi, M.; Cerocchi, I.; Iundusi, R. Incidence of fragility fractures aging Aging Clin. Exp. Res. 2007, 19, 7-11
3. Cummings, S. R.; Melton, L. J. Epidemiology and outcomes of osteoporotic fractures Lancet 2002, 359, 1761-1767
4. Black, D. M.; Cummings, S. R.; Karpf, D. B.; Cauley, J. A.; Thompson, D. E.; Nevitt, M. C.; Bauer, D. C.; Genant, H. K.; Haskell, W. L.; Marcus, R.; Ott, S. M.; Torner, J. C.; Quandt, S. A.; Reiss, T. F.; Ensrud, K. E.; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures Lancet 1996, 348, 1535-1541 (Pubitemid 26411651)
5. Reginster, J.; Minne, H. W.; Sorensen, O. H.; Hooper, M.; Roux, C.; Brandi, M. L.; Lund, B.; Ethgen, D.; Pack, S.; Roumagnac, I.; Eastell, R.; On behalf of the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis Osteoporosis Int. 2000, 11, 83-91 (Pubitemid 30099515)
6. Ettinger, B.; Black, D. M.; Mitlak, B. H.; Knickerbocker, R. K.; Nickelsen, T.; Genant, H. K.; Christiansen, C.; Delmas, P. D.; Zanchetta, J. R.; Stakkestad, J.; Glüer, C. C.; Krueger, K.; Cohen, F. J.; Eckert, S.; Ensrud, K. E.; Avioli, L. V.; Lips, P.; Cummings, S. R.; Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial JAMA, J. Am. Med. Assoc. 1999, 282, 637-645 (Pubitemid 29384151)
7. Pleiner-Duxneuner, J.; Zwettler, E.; Paschalis, E.; Roschger, P.; Nell-Duxneuner, V.; Klaushofer, K. Treatment of osteoporosis with parathyroid hormone and teriparatide Calcif. Tissue Int. 2009, 84, 159-170
8. Dobnig, H. A review of teriparatide and its clinical efficacy in the treatment of osteoporosis Expert Opin. Pharmacother. 2004, 5, 1153-1162 (Pubitemid 38702343)
9. Neer, R. M.; Arnaud, C. D.; Zanchetta, J. R.; Prince, R.; Gaich, G. A.; Reginster, J. Y.; Hodsman, A. B.; Eriksen, E. F.; Ish-Shalom, S.; Genant, H. K.; Wang, O.; Mitlak, B. H. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis N. Engl. J. Med. 2001, 344, 1434-1441 (Pubitemid 32402100)
10. Lotinun, S.; Sibonga, J. D.; Turner, R. T. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression Endocrine 2002, 17, 29-36 (Pubitemid 34311421)
11. Frolik, C. A.; Black, E. C.; Cain, R. L.; Satterwhite, J. H.; Brown-Augsburger, P. L.; Sato, M.; Hock, J. M. Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure Bone 2003, 33, 372-379 (Pubitemid 37103254)
12. Gerspacher, M; Altmann, E; Beerli, R; Buhl, T; Endres, R; Gamse, R; Kameni-Tcheudji, J; Kneissel, M; Krawinkler, K. H.; Missbach, M; Schmidt, A; Seuwen, K; Weiler, S; Widler, L. Penta-substituted benzimidazoles as potent antagonists of the calcium-sensing receptor (CaSR-antagonists) Bioorg. Med. Chem. Lett. 2010, 17, 5161-5164
13. Chattopadhyay, N. Biochemistry, physiology and pathophysiology of the extracellular calcium-sensing receptor Int. J. Biochem. Cell Biol. 2000, 32, 789-804 (Pubitemid 30625115)
14. Fox, J.; Miller, M. A.; Stroup, G. B.; Nemeth, E. F.; Miller, S. C. Plasma levels of parathyroid hormone that induce anabolic effects in bone of ovariectomized rats can be achieved by stimulation of endogenous hormone secretion Bone 1997, 21, 163-169 (Pubitemid 27395404)
15. Gowen, M.; Stroup, G. B.; Dodd, R. A.; James, I. E.; Votta, B. J.; Smith, B. R.; Bhatnagar, P. K.; Lago, A. M.; Callahan, J. F.; DelMar, E. G.; Miller, M. A.; Nemeth, E. F.; Fox, J. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats J. Clin. Invest. 2000, 105, 1595-1604 (Pubitemid 30390310)
16. Kumar, S.; Matheny, C. J.; Hoffman, S. J.; Marquis, R. W.; Schultz, M.; Liang, X.; Vasko, J. A.; Stroup, G. B.; Vaden, V. R.; Haley, H.; Fox, J.; Delmar, E. G.; Nemeth, E. F.; Lago, A. M.; Callahan, J. F.; Bhatnagar, P.; Huffman, W. F.; Gowen, M.; Yi, B.; Danoff, T. M.; Fitzpatrick, L. A. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation Bone 2010, 46, 534-542
17. Carter, P. H.; Liu, R. Q.; Foster, W. R.; Tamasi, J. A.; Tebben, A. J.; Favata, M.; Staal, A.; Cvijic, M. E.; French, M. H.; Dell, V.; Apanovitch, D.; Lei, M.; Zhao, Q.; Cunningham, M.; Decicco, C. P.; Trzaskos, J. M.; Feyen, J. H. Discovery of a small molecule antagonist of the parathyroid hormone receptor by using an N-terminal parathyroid hormone peptide probe Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 6846-6851 (Pubitemid 47175589)
18. Yoshida, M.; Mori, A.; Inaba, A.; Oka, M.; Makino, H.; Yamaguchi, M.; Fujita, H; Kawamoto, T.; Goto, M.; Kimura, H.; Baba, A.; Yasuma, T. Synthesis and structure-activity relationship of tetrahydropyrazolopyrimidine derivatives - a novel structural class of potent calcium-sensing receptor antagonists Bioorg. Med. Chem. 2010, 18, 8501-8511
19. X-ray crystallographic data for compound 17c has been deposited with the Cambridge Crystallographic Data Center as CCDC 800340. The crystallographic data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac. uk).
20. Fox, J.; Miller, M. A.; Newman, M. K.; Metcalfe, A. F.; Turner, C. H.; Recker, R. R.; Smith, S. Y. Daily treatment of aged ovariectomized rats with human parathyroid hormone (1-84) for 12 months reverses bone loss and enhances trabecular and cortical bone strength Calcif. Tissue Int. 2006, 79, 262-272 (Pubitemid 44673720)