title: Discovery of a calcimimetic with differential effects on parathyroid hormone and calcitonin secretion.
abstract: Calcimimetics are positive allosteric modulators to the calcium-sensing receptor (CaSR). Activation of the CaSR inhibits the secretion of parathyroid hormone (PTH), stimulates the secretion of calcitonin, and decreases serum calcium (Ca(2+)). Cinacalcet, a second-generation calcimimetic, is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism. A calcimimetic that displays increased separation of PTH versus Ca(2+) lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population. Toward this end, we developed a third-generation calcimimetic, determined the molecular pharmacological properties of it using an operation model of allosteric modulation/agonism, and measured the compound effects on PTH, serum ionized Ca(2+), and calcitonin levels in 5/6 nephrectomized rats. We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia. Furthermore, our third-generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine (R-568), a first-generation calcimimetic. These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion.
authors.affiliation: Department of Metabolic Disorders, Amgen Thousand Oaks, Thousand Oaks, California, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Henley
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Davis
authors.forename: Jenny Ying Lin
authors.initials: JY
authors.lastname: Lu
authors.forename: Sean
authors.initials: S
authors.lastname: Morony
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Monica
authors.initials: M
authors.lastname: Florio
authors.forename: Banghua
authors.initials: B
authors.lastname: Sun
authors.forename: Edward
authors.initials: E
authors.lastname: Shatzen
authors.forename: James K
authors.initials: JK
authors.lastname: Pretorius
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D002116:Calcitonin / Q000097:blood / Q000378:metabolism*; D002118:Calcium / Q000819:agonists* / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004048:Diethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000209:etiology; D006996:Hypocalcemia / Q000150:complications; D007295:Inositol Phosphates / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism*; D010627:Phenethylamines; D010766:Phosphorylation / Q000187:drug effects; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects
chemical_list: C559488:1-(6-methoxy-4'-(trifluoromethyl)-3-biphenylyl)-N-(1-phenylethyl)ethanamine; D000814:Aniline Compounds; D001713:Biphenyl Compounds; D004048:Diethylamines; D007295:Inositol Phosphates; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D002116:Calcitonin; D002118:Calcium