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Published Online:https://doi.org/10.4155/fmc.11.17

The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium-sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone. Provided the effect of the calcilytic is of short duration, a bone anabolic effect should also result. Although the first calcilytic series became known approximately 10 years ago, the number of different structural types is still small today. This article outlines the quest from hits to potent development candidates of all relevant calcilytic series currently known. Even after the front-runners unexpectedly failed in the clinic, the approach for an oral alternative to parenteral PTH remains highly attractive.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

  • Berry SD, Kiel DP, Donaldson MG et al. Application of the National Osteoporosis Foundation guidelines to postmenopausal women and men: the Framingham osteoporosis study. Osteoporosis Int.21,53–60 (2010).
  • Ray NF, Chan JK, Thamer M, Melton LJ. Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation. J. Bone Miner. Res.12,24–35 (1997).
  • Tarantino U, Cannata G, Lecce D, Celi M, Cerocchi I, Lundusi R. Incidence of fragility fractures. Aging Clin. Exp. Res.19(Suppl. 4),7–11 (2007).
  • Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone40,1434–1446 (2007).
  • Russell RG, Espina B, Hulley P. Bone biology and the pathogenesis of osteoporosis. Curr. Opin. Rheumatol.18(Suppl. 1),S3–S10 (2006).
  • Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med.357,905–916 (2007).
  • Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med.11,76–81 (2005).
  • Neer RM, Arnaud DC, Zanchetta JR et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med.344,1434–1341 (2001).
  • File E, Deal D. Clinical update on teriparatide. Curr. Rheumatol. Reports11,169–176 (2009).
  • 10  Blick SK, Dhillon S, Keam SJ. Teriparatide: a review of its use in osteoporosis. Drugs68,2709–2737 (2008).
  • 11  Stroup J, Kane MP, Abu-Baker AM. Teriparatide in the treatment of osteoporosis. Am. J. Health Syst. Pharm.65,532–539 (2008).
  • 12  Horowitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, Stewart AF. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J. Clin. Endocrinol. Metab.88,569–575 (2003).
  • 13  O’Dea L, Lyttle CR, Rosen CJ. BA058, a novel analog of human parathyroid hormone-related peptide (PTHrP), induces evidence of bone formation without evidence of bone resorption over 7 days of exposure. Presented at: The 89th Annual Meeting of the Endocrine Society, Abstract P2–137. Toronto, ON, Canada, 2–5 June 2007.
  • 14  Fox J. Developments in parathyroid hormone and related peptides as bone-formation agents. Curr. Opin. Pharmacol.2,338–344 (2002).
  • 15  Morley P. Delivery of parathyroid hormone for the treatment of osteoporosis. Expert Opin. Drug Deliv.2,993–1002 (2005).
  • 16  Tashjian AH, Goltzman D. On the interpretation of rat carcinogenicity studies for human PTH(1–34) and human PTH(1–84). J. Bone Miner. Res.23,803–811 (2008).
  • 17  Trivedi R, Mitah A, Chattopadhyay N. Recent updates on the calcium-sensing receptor as a drug target. Curr. Med. Chem.15,178–186 (2008).
  • 18  Brown EM. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell. Biochem.45,139–165 (2007).▪ Comprehensive review of biology, disorders and therapeutics based on the calcium-sensing receptor.
  • 19  Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocrine Rev.14,690–709 (1993).
  • 20  Qin L, Raggatt LJ, Partridge NC. Parathyroid hormone: a double-edged sword for bone metabolism. Trends Endocrinol. Metab.15,60–65 (2004).▪ Effect of parathyroid hormone on bone: anabolic or catabolic action depending on exposure time.
  • 21  Loitnun S, Sibonga J, Turner R. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression. Endocrine17,29–36 (2002).
  • 22  Frolik CA, Black EC, Cain RL et al. Anabolic and catabolic effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone33,372–379 (2003).
  • 23  Kramer I, Keller H, Leupin O, Kneissel M. Does osteocytic SOST suppression mediate PTH bone anabolism? Trends Endocrinol. Metab.21,237–244 (2010).
  • 24  Goltzman D. Studies on the mechanisms of the skeletal anabolic action of endogenous and exogenous parathyroid hormone. Arch. Biochem. Biophys.473,218–224 (2008).
  • 25  Poole KE, Reeve J. Parathyroid hormone – a bone anabolic and catabolic agent. Curr. Opin. Pharmacol.5,612–617 (2005).
  • 26  Messa P, Alfieri C, Brezzi B. Cinacalcet: pharmacological and clinical aspects. Expert Opin. Drug Metabol. Toxicol.4,1551–1560 (2008).
  • 27  Harrington P, Fotsch C. Calcium sensing receptor activators: calcimimetics. Curr. Med. Chem.14,3027–3034 (2007).
  • 28  Nemeth EF. The search for calcium receptor antagonists (calcilytics). J. Mol. Endocrinol.29,15–21 (2002).
  • 29  Nemeth EF. Anabolic therapy for osteoporosis: calcilytics. Bonekey Osteovision5(6),196–208 (2008).▪▪ Brief review of calcilytics: concept, molecular structures and clinical results.
  • 30  Nemeth EF. Drugs acting on the calcium receptor. In: Principles of Bone Biology (3rd Edition). Bilezikian JP, Raisz LG, Martin TJ (Eds). Elsevier, San Diego, CA, USA 1711–1735 (2008).
  • 31  Trivedi R, Mithal A, Chattopadhyay N. Pharmacological manipulation of calcium-sensing receptor: prospect as anabolic therapy for postmenopausal osteoporosis. Drugs Fut.34,803–809 (2009).▪▪ Brief but most comprehensive review of calcilytic compounds.
  • 32  Allen JG, Fotsch C, Babij P. Emerging targets in osteoporosis disease modification. J. Med. Chem.53,4332–4353 (2010).
  • 33  Marquis RW, Lago AM, Callahan JF et al. Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues. J. Med. Chem.52,3982–3993 (2009).
  • 34  Gowen M, Stroup GB, Dodds RA et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest.105,1595–1604 (2000).
  • 35  Nemeth EF, Delmar EG, Heaton WL et al. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther.299,323–331 (2001).
  • 36  Marquis RW, Lago AM, Callahan JF et al. Antagonists of the calcium receptor II. Amino alcohol-based parathyroid hormone secretagogues. J. Med. Chem.52,6599–6605 (2009).▪ Incorporation of a polar carboxylic acid moiety into the amino-alcohol structure significantly improves the selectivity and the pharmacokinetic profile of NPS 2143 (ronacaleret and analogs).
  • 37  Kumar S, Matheny CJ, Hoffman SJ et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone46,534–542 (2010).
  • 38  Fitzpatrick LA, Brennan E, Kumar S et al. Ronacaleret, a novel calcium-sensing receptor antagonist, demonstrates potential as an oral bone-forming therapy in healthy postmenopausal women. J. Bone Miner. Res.23(Suppl. 50), (2008).
  • 39  Glover SJ, Eastell R, McCloskey EV et al. Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone45,1053 (2009).
  • 40  Lindsay R, Nieves J, Henneman E, Shen V, Cosman F. Subcutaneous administration of the amino-terminal fragment of human parathyroid hormone-(1–34): kinetics and biochemical response in estrogenized oseoporotic patients. J. Clin. Endocrinol. Metab.77,1535–1539 (1993).
  • 41  Fitzpatrick L, Dabrowski C, Cicconetti G et al. Ronacaleret, a calcium-sensing receptor antagonist: results of a 1 year double-blind, placebo-controlled, dose ranging phase II study. J. Bone Miner. Res.24(Suppl. 1), Abstract 1130 (2009).
  • 42  Shinagawa Y, Inoue T, Hirata K et al. New aminopropandiol derivatives as orally available and short-acting calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett.20,3809–3813 (2010).
  • 43  Shinagawa Y, Inoue T, Katsushima T et al. Discovery of a potent and short-acting oral calcilytic with a pulsatile secretion of parathyroid hormone. ACS Med. Chem. Lett. DOI: 10.1021/ml100268k (2010) (Epub ahead of print).
  • 44  Fukumoto S, Nakamura T, Nishizawa Y, Hayashi M, Matsumoto R. JTT-305 shows promise for the treatment of hypocalcemia and osteoporosis. J. Bone Miner. Res.24(Suppl. 1), Abstract 1131 (2009).
  • 45  Balan G, Bauman J, Bhattacharya S et al. The discovery of novel calcium sensing receptor negative allosteric modulators. Bioorg. Med. Chem.19,3328–3332 (2009).
  • 46  Bodor N, Buchwald P. Soft drug design: general principles and recent applications. Med. Res. Rev.20,58–101 (2000).
  • 47  Southers JA, Bauman JN, Price DA et al. Metabolism-guided design of short-acting calcium-sensing receptor antagonists. ACS Med. Chem. Lett.1,219–223 (2010).
  • 48  Yang W, Wang Y, Roborge JY, Ma Z et al. Discovery and structure–activity relationships of 2-benzlypyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett.15,1225–1228 (2005).
  • 49  Gavai AV, Vaz RJ, Mikkilineni AB et al. Discovery of novel 1-arylmethylpyrrolidin-2-ylethanolamines as calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett.15,5478–5482 (2005).
  • 50  Kessler A, Faure H, Roussanne MC et al. N1-arylsulfonyl-N2-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexanes: a new class of calcilytic agents acting at the calcium-sensing receptor. ChemBioChem4,1131–1136 (2004).
  • 51  Kessler A, Faure H, Petrel C et al. N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: development of 4-chlorophenylcarboxamide (Calhex 231) as a new calcium sensing receptor ligand demonstrating potent calcilytic activity. J. Med. Chem.49,5119–5128 (2006).▪ Structure–activity relationship study leading to Calhex231 at the Centre National de la Recherche Scientifique (CNRS).
  • 52  Yang W, Ruan Z, Wang Y et al. Discovery and structure–activity relationships of trisubstituted pyrimidines/pyridines as novel calcium-sensing receptor antagonists. J. Med. Chem.52,1204–1208 (2009).▪ Pyrimidine/pyridine series developed by Bristol-Myers Squibb.
  • 53  Arey BJ, Seethala R, Ma Z et al. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology146,2015–2022 (2005).
  • 54  Shcherbakova I, Balandrin MF, Fox J et al. 3H-quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis. Bioorg. Med. Chem. Lett.15,1557–1560 (2005).
  • 55  Kalgutkar AS, Griffith DA, Ryder T et al. Discovery tactics to mitigate toxicity risks due to reactive metabolite formation with 2-(2-hydroxyaryl)-5-(trifluoromehtyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives, potent calcium-sensing receptor antagonists and clinical candidate(s) for the treatment of osteoporosis. Chem. Res. Toxicol.23,1115–1126 (2010).
  • 56  Shcherbakova I, Huang G, Geoffroy OJ et al. Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones. Bioorg. Med. Chem. Lett.15,2537–2540 (2005).▪ From quinazolin-4-ones to pyrimidinones, a back-up series developed at NPS Pharmaceuticals.
  • 57  Didiuk MT, Griffith DA, Benbow JW et al. Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally -active calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett.19,4555–4559 (2009).▪ Structure–activity relationship study of the quinazolin-4-one series developed by Pfizer.
  • 58  Coombs RV, Danna RP, Denzer M et al. Synthesis and antiinflammatory activity of 1-alkyl-4-aryl-2(1H)-quinazolinones and quinazolinethiones. J. Med. Chem.16,1237–1245 (1973).
  • 59  Houlihan WJ, Cooke G, Van Bochoven R, Perrine J, Takesue EI, Jukniewicz EJ. Anti-inflammatory properties of 8-aryl-5-isopropyl-2H-1,3-dioxolo[4,5-g]quinazolin-6(5H)-ones and -thiones. J. Med. Chem.25,1110–1113 (1982).
  • 60  Perrine JW, Houlihan WJ, Takesue EI. Antiinflammatory and other pharmacodynamic properties of five members of the 4-aryl-1-isopropyl-2(1H)-quinazolinone series. Arzneimittelforschung34(8),879–885 (1984).
  • 61  Widler L, Altmann E, Beerli R et al. 1-alkyl-4-phenyl-6-alkoxy-1H-quinazoline-2-ones: a novel series of potent calcium-sensing receptor antagonists. J. Med. Chem.53,2250–2263 (2010).▪▪ Review paper on the discovery and development of the Novartis quinazolin-2-ones series.
  • 62  John M, Widler L, Gamse R et al. ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone (In Press).
  • 63  Widler L, Gamse R, Seuwen K et al. A novel calcium-sensing receptor antagonist leads to dose-dependent transient release of parathyroid hormone after oral administration to healthy volunteers – an initial proof-of-concept for a potential new class of anabolic osteoporosis therapeutics. J. Bone Miner. Res.23(Suppl. 49), (2008).
  • 64  John M, Harfst E, Loeffler J et al. A 4-week study of AXT914, a novel calcilytic compound for oral bone anabolic osteoporosis therapy, in postmenopausal women. J. Bone Miner. Res.25(Suppl. 1),S332 (2010).
  • 65  Gerspacher M, Altmann E, Beerli R et al. Penta-substituted benzimidazoles as potent antagonists of the calcium sensing receptor (CaSR-antagonists). Bioorg. Med. Chem. Lett.20,5161–5164 (2010).
  • 66  Petrel C, Kessler A, Mashlah F et al. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca2+-sensing receptor. J. Biol. Chem.278,49487–49494 (2003).
  • 67  Petrel C, Kessler A, Dauban P, Dodd RH, Rogan D, Ruat M. Positive and negative allosteric modulators of the Ca2+-sensing receptor. J. Biol. Chem.279,18990–18997 (2004).
  • 68  Miedlich SU, Gama L, Seuwen K, Wolf RM, Breitwieser GE. Homology modeling of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site. J. Biol. Chem.279,7254–7263 (2004).
  • 69  Bu L, Michino M, Wolf RM, Brooks CL. Improved model building and assessment of the calcium-sensing receptor transmembrane domain. Proteins71,215–226 (2008).
  • 70  Hu J, Jiang J, Costanzi S et al. A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator. J. Biol. Chem.281,21558–21565 (2006).
  • 71  Magno AL, Ward BK, Ratajczak T. The calcium-sensing receptor: a molecular perspective. Endoc. Rev.32(1),3–30 (2010).
  • 72  Brown EM. Clinical lessons from the calcium-sensing receptor. Nat.Rev. Endocrinol.3,122–133 (2007).
  • 73  Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathopyhsiology. Clin. Rev. Clin. Lab. Sci.42,35–70 (2005).
  • 74  Geibel JP, Hebert SC. The functions and roles of the extracellular Ca2+-sensing receptor along the gastrointestinal tract. Annu. Rev. Physiol.71,205–217 (2009).
  • 75  Ba J, Friedman PA. Calcium-sensing receptor regulation of renal mineral ion transport. Cell Calcium35,229–237 (2004).
  • 76  Weston AH, Absi M, Ward DT et al. Evidence in favor of a calcium-sensing receptor in arterial endothelial cells. Circ. Res.97,391–398 (2005).
  • 77  Chakravarti B, Dwivedi SKD, Mithal A, Chattopadhyay N. Calcium-sensing receptor in cancer: good cop or bad cop? Endocrine35,271–284 (2009).
  • 78  Rodland KD. The role of the calcium-sensing receptor in cancer. Cell Calcium35,291–295 (2004).
  • 79  Bandyopadhyay S, Tfelt-Hansen J, Chattopadhyay N. Diverse roles of extracellular calcium-sensing receptor in the central nervous system. J. Neurosci. Res.88,2073–2082 (2010).
  • 80  Brown EM. Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium. Endocrinol. Metab. Clin. North Am.29,503–523 (2000).
  • 101  Smithkline Beecham Co. WO2010055631 (2009).
  • 102  Japan Tobacco Inc. WO0214259 (2002).
  • 103  Japan Tobacco Inc. WO2004094362 (2004).
  • 104  Japan Tobacco Inc. WO2004106280 (2004).
  • 105  Daiichi Sankyo Co. WO2010074089 (2010).
  • 106  Asahi Kasai Pharma Corp. WO2009148052 (2009).
  • 107  Novartis AG. WO2008107390 (2008).
  • 108  Novartis AG WO2007020046 (2007).
  • 201  De Lano WL. The PyMol Molecular Graphics System, Version 1.0r2. DeLano Scientific LLC. San Carlos, CA, USA. www.pymol.org