The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
William G Goodman - One of the best experts on this subject based on the ideXlab platform.
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Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease?
Current opinion in nephrology and hypertension, 2005Co-Authors: William G GoodmanAbstract:Purpose of reviewCinacalcet is a Calcimimetic Agent that is now available for use clinically to manage secondary hyperparathyroidism among patients undergoing dialysis regularly. It acts as an allosteric activator of the calcium-sensing receptor, the molecular mechanism that controls parathyroid hor
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Calcimimetic Agents and secondary hyperparathyroidism: rationale for use and results from clinical trials
Pediatric Nephrology, 2003Co-Authors: William G GoodmanAbstract:Calcimimetic Agents are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR). In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. Calcimimetic compounds thus represent a novel way of controlling excess PTH secretion in clinical disorders such as secondary hyperparathyroidism (SHPT) due to chronic renal failure. Clinical trials have documented that the Calcimimetic Agent cinacalcet hydrochloride effectively lowers plasma PTH levels without increasing serum calcium or phosphorus concentrations in adult hemodialysis patients with SHPT. Serum phosphorus levels and values for the calcium-phosphorus ion product in serum often decline as plasma PTH levels fall during treatment. Experimental evidence suggests that Calcimimetic Agents may also impede the development of parathyroid gland hyperplasia, an integral component of SHPT due to chronic renal failure. Calcimimetic Agents have considerable potential, therefore, as part of new therapeutic strategies for SHPT.
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The Calcimimetic Agent AMG 073 Lowers Plasma Parathyroid Hormone Levels in Hemodialysis Patients with Secondary Hyperparathyroidism
Journal of the American Society of Nephrology : JASN, 2002Co-Authors: William G Goodman, David A Goodkin, Stewart A Turner, Wei Liu, Gerald A. Hladik, Peter W. Blaisdell, Yousri M. Barri, Raphael M. Cohen, Jack W CoburnAbstract:ABSTRACT. Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in many patients with secondary hyperparathyroidism due to end-stage renal disease, but hypercalcemia, hyperphosphatemia, or both often develop during treatment. As such, alternative therapeutic approaches to managing excess PTH secretion are needed. Calcimimetic Agents directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands, but clinical experience with them is limited. Fifty-two hemodialysis patients with secondary hyperparathyroidism were given single orally administered doses of the Calcimimetic Agent AMG 073 ranging from 5 to 100 mg, or placebo. Plasma PTH levels decreased 2 h after 25-, 50-, 75-, or 100-mg doses, falling by a maximum of 43 ± 29%, 40 ± 36%, 54 ± 28%, or 55 ± 39%, respectively. Plasma PTH levels decreased in all patients given doses of ≥25 mg but did not change in those who received placebo. In patients treated with daily doses of 25 or 50 mg of AMG 073 for 8 d, plasma PTH levels declined for the first 3 to 4 d and remained below baseline values after 8 d of treatment. Serum calcium concentrations also decreased by 5 to 10% from pretreatment levels in patients given 50 mg of AMG 073 for 8 d, but values were unchanged in those who received lower doses. Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073. Thus, 8 d of treatment with AMG 073 effectively lowers plasma PTH levels and improves several disturbances in mineral metabolism that have been associated with soft tissue and vascular calcification and with adverse cardiovascular outcomes in patients with end-stage renal disease.
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Future Role of Calcimimetics in End-Stage Renal Disease
Advances in renal replacement therapy, 2002Co-Authors: William G Goodman, Stewart A TurnerAbstract:Calcimimetic Agents are small organic molecules that act as allosteric activators of the calcium-sensing receptor. In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. These compounds offer a novel way of controlling excess PTH secretion in clinical disorders associated with excess PTH secretion, including secondary hyperparathyroidism due to chronic renal failure. The first Calcimimetic Agent to be evaluated in clinical trials was R-568, but studies were discontinued because of its limited bioavailability and inconsistent pharmacokinetic profile. Extensive assessments are currently underway by using a second-generation Calcimimetic compound, AMG 073, to treat secondary hyperparathyroidism. Work completed thus far has shown that AMG 073 effectively lowers plasma PTH, without increasing values for the calcium-phosphorus ion product in serum in patients with end-stage renal disease. Indeed, serum phosphorus levels often decline as plasma PTH levels fall during treatment. Recent experimental evidence also suggests that Calcimimetic Agents may impede the development of parathyroid gland hyperplasia, an integral component of secondary hyperparathyroidism due to chronic renal failure. Calcimimetics Agents have considerable potential therefore as a new approach to the medical management secondary hyperparathyroidism.
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a Calcimimetic Agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism
Kidney International, 2000Co-Authors: William G Goodman, Joao M Frazao, David A Goodkin, Stewart A Turner, Wei Liu, Jack W CoburnAbstract:A Calcimimetic Agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Background The Calcimimetic Agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. Methods Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 ( N = 16) or placebo ( N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. Results Pretreatment PTH levels were 599 ± 105 (mean ± SE) and 600 ± 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 ± 5%, 78 ± 3%, and 70 ± 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 ± 70 and 443 ± 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. Conclusions The Calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.
Paul Evans - One of the best experts on this subject based on the ideXlab platform.
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An Investigation into the One-Pot Heck Olefination—Hydrogenation Reaction.
ChemInform, 2011Co-Authors: Kimberly Geoghegan, Susan M. Kelleher, Paul EvansAbstract:The reaction allows a simple and effective access to a number of compounds and can be applied successfully to prepare the Calcimimetic Agent cinacalcet (X).
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An Investigation into the One-Pot Heck Olefination-Hydrogenation Reaction
The Journal of organic chemistry, 2011Co-Authors: Kimberly Geoghegan, Susan M. Kelleher, Paul EvansAbstract:Herein is described an operationally simple process concerning the observation that, following either inter-, or intramolecular Heck olefination, stirring of the so formed substituted alkenyl product under an atmosphere of hydrogen efficiently effects alkene hydrogenation. Overall this two-operation, one-pot “reductive Heck” sequence is notable since direct reductive Heck processes, using additives such as formate salts, are restricted to a limited range of substrates. In total 25 examples are reported (yields ranging from 0 to 95%), which were selected in order to probe the scope and limitations of this method. Finally, the utility of this sequence was demonstrated in a short synthesis of the Calcimimetic Agent, cinacalcet.
V. Hadjiconstantinou - One of the best experts on this subject based on the ideXlab platform.
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hypercalcemia due to resistant hyperparathyroidism in renal transplant patients treated with the Calcimimetic Agent cinacalcet
Transplantation proceedings, 2006Co-Authors: T. Apostolou, L. Damianou, V. Kotsiev, K. Kollia, H. Kaitsioti, S. Dracopoulos, V. Vougas, V. HadjiconstantinouAbstract:Abstract Introduction and aims Calcimimetic Agents increase the sensitivity of calcium-sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone (PTH). The use of these drugs in patients with a functioning graft suffering from resistant hyperparathyroidism and hypercalcemia is still under investigation. We report seven patients who were treated with the Calcimimetic Agent cinacalcet. Methods The four male and three female patients of 38 to 72 years of age received a renal transplant from 4 to 35 months before cinacalcet treatment. Serum creatinine was 1.2 to 1.8 mg/dL (estimated glomerular filtration rate between 40 and 75 mL/min). Immunosuppressive treatment consisted of interleukin-2 antibody induction therapy, calcineurin inhibitors (cyclosporine or tacrolimus), prednisolone, and mycophenolate mofetil. Mild to severe hyperparathyroidism resistant to vitamin D analog treatment (intact parathyroid hormone molecule [iPTH] 174 to 519 pg/mL) was accompanied by severe hypercalcemia (Ca >11 mg%). To date the patients have completed 3 to 18 months of therapy. Cinacalcet 30 mg/d was initially administered. Results This treatment resulted in a rapid decrease in total serum calcium (8.6 to 9.2 mg/dL) while PTH showed a milder, progressive decrease. Having controlled calcium levels, 1α OH vitamin D (0.25 μg/d per os) was added to the treatment, which resulted in a further decline of iPTH without producing an increase in serum calcium concentrations (median initial iPTH value 401 pg/mL, median value after treatment 176 pg/mL). Therapy was well tolerated without hypocalcemic events. Conclusion Cinacalcet offered a better holistic treatment approach to such patients.
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Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the Calcimimetic Agent cinacalcet.
Clinical nephrology, 2006Co-Authors: T. Apostolou, L. Damianou, V. Kotsiev, S. Drakopoulos, V. HadjiconstantinouAbstract:Calcimimetic Agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with Calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium < 10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the Calcimimetic Agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH
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treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the Calcimimetic Agent cinacalcet
Clinical Nephrology, 2006Co-Authors: T. Apostolou, L. Damianou, V. Kotsiev, S. Drakopoulos, V. HadjiconstantinouAbstract:Calcimimetic Agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with Calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium < 10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the Calcimimetic Agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new Agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.
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Hypercalcemia due to resistant hyperparathyroidism in renal transplant patients treated with the Calcimimetic Agent cinacalcet.
Transplantation proceedings, 2006Co-Authors: T. Apostolou, L. Damianou, V. Kotsiev, K. Kollia, H. Kaitsioti, S. Dracopoulos, V. Vougas, V. HadjiconstantinouAbstract:Calcimimetic Agents increase the sensitivity of calcium-sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone (PTH). The use of these drugs in patients with a functioning graft suffering from resistant hyperparathyroidism and hypercalcemia is still under investigation. We report seven patients who were treated with the Calcimimetic Agent cinacalcet. The four male and three female patients of 38 to 72 years of age received a renal transplant from 4 to 35 months before cinacalcet treatment. Serum creatinine was 1.2 to 1.8 mg/dL (estimated glomerular filtration rate between 40 and 75 mL/min). Immunosuppressive treatment consisted of interleukin-2 antibody induction therapy, calcineurin inhibitors (cyclosporine or tacrolimus), prednisolone, and mycophenolate mofetil. Mild to severe hyperparathyroidism resistant to vitamin D analog treatment (intact parathyroid hormone molecule [iPTH] 174 to 519 pg/mL) was accompanied by severe hypercalcemia (Ca >11 mg%). To date the patients have completed 3 to 18 months of therapy. Cinacalcet 30 mg/d was initially administered. This treatment resulted in a rapid decrease in total serum calcium (8.6 to 9.2 mg/dL) while PTH showed a milder, progressive decrease. Having controlled calcium levels, 1alpha OH vitamin D (0.25 microg/d per os) was added to the treatment, which resulted in a further decline of iPTH without producing an increase in serum calcium concentrations (median initial iPTH value 401 pg/mL, median value after treatment 176 pg/mL). Therapy was well tolerated without hypocalcemic events. Cinacalcet offered a better holistic treatment approach to such patients.
Masafumi Fukagawa - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients
Clinical and Experimental Nephrology, 2019Co-Authors: Kazuhiko Tsuruya, Masafumi Fukagawa, Ryutaro Shimazaki, Tadao AkizawaAbstract:Background Secondary hyperparathyroidism (SHPT) is a serious and common complication in patients receiving peritoneal dialysis (PD). Cinacalcet is currently the recommended therapy for SHPT; however, gastrointestinal (GI)-related symptoms can result in low adherence and high discontinuation rates. Evocalcet is a novel Calcimimetic Agent that has non-inferior efficacy while providing a more tolerable safety profile. Methods This was a multicenter, intra-subject dose-adjustment treatment study evaluating the efficacy and safety of 1–8 mg evocalcet orally administered once daily for 32 weeks for the treatment of SHPT in PD patients. Patients then entered a 20-week extension period (dose range 1–12 mg). The primary endpoint was the proportion of patients who achieved a mean intact parathyroid hormone (iPTH) level of 60–240 pg/mL during the evaluation period (weeks 30–32). Secondary efficacy endpoints included the proportion of patients achieving ≥ 30% decrease in iPTH levels. Results A total of 39 Japanese PD patients with SHPT received evocalcet. The target mean iPTH level of 60–240 pg/mL was achieved by 71.8% (28/39) of patients during the evaluation period and 83.3% (20/24) of patients at week 52. The proportion of patients who achieved ≥ 30% decrease in iPTH levels from baseline was 74.4% (29/39) during the evaluation period and 87.5% (21/24) at week 52. Adverse drug reactions occurred in 46.2% (18/39) of patients, with most being of mild-to-moderate severity including GI-related events. Conclusion This study shows the long-term efficacy and safety of evocalcet when orally administered to PD patients with SHPT once daily. Clinical trial registration ClinicalTrials.gov: NCT02549417, https://clinicaltrials.gov/ct2/show/NCT02549417 ; JAPIC: JapicCTI-153016, http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-153016 .
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Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study
Clinical Drug Investigation, 2018Co-Authors: Tadao Akizawa, Ryutaro Shimazaki, Masanari Shiramoto, Masafumi FukagawaAbstract:Background and Objectives Evocalcet is a novel Calcimimetic Agent with potential to improve the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. This study aimed to determine the pharmacokinetics, pharmacodynamics, and safety of evocalcet in healthy Japanese subjects. Methods This was a single-blind, placebo-controlled, single-dose study and an 8-day multiple-dose study of evocalcet (MT-4580/KHK7580) in 66 healthy Japanese subjects. Results After a single dose of evocalcet 1–20 mg, the time to maximum plasma concentration was attained in 1.5–2 h (median), and the elimination half-life was 12.98–19.77 h (mean). Within this dose range, the maximum plasma concentration and area under plasma concentration-time curve increased dose proportionally, confirming linearity. The trough plasma concentrations were relatively unchanged after multiple administration of evocalcet 6 and 12 mg. Evocalcet decreased intact parathyroid hormone and corrected calcium and phosphorus levels in a dose-proportional manner. Regarding its safety, no upper gastrointestinal adverse event occurred after the single and multiple administration of evocalcet at doses up to 12 mg. Tetany was detected in 1 subject (17%) after multiple administration of evocalcet 12 mg. In healthy subjects, the tolerability and safety of evocalcet were observed for a single dose of evocalcet at doses up to 20 mg, and for multiple doses up to 12 mg. Conclusions These results suggest that evocalcet may have a comparable efficacy and better safety profile than that of cinacalcet, one of the current treatments for secondary hyperparathyroidism in patients with chronic kidney disease.
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Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study.
Clinical drug investigation, 2018Co-Authors: Tadao Akizawa, Ryutaro Shimazaki, Masanari Shiramoto, Masafumi FukagawaAbstract:Evocalcet is a novel Calcimimetic Agent with potential to improve the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. This study aimed to determine the pharmacokinetics, pharmacodynamics, and safety of evocalcet in healthy Japanese subjects. This was a single-blind, placebo-controlled, single-dose study and an 8-day multiple-dose study of evocalcet (MT-4580/KHK7580) in 66 healthy Japanese subjects. After a single dose of evocalcet 1–20 mg, the time to maximum plasma concentration was attained in 1.5–2 h (median), and the elimination half-life was 12.98–19.77 h (mean). Within this dose range, the maximum plasma concentration and area under plasma concentration-time curve increased dose proportionally, confirming linearity. The trough plasma concentrations were relatively unchanged after multiple administration of evocalcet 6 and 12 mg. Evocalcet decreased intact parathyroid hormone and corrected calcium and phosphorus levels in a dose-proportional manner. Regarding its safety, no upper gastrointestinal adverse event occurred after the single and multiple administration of evocalcet at doses up to 12 mg. Tetany was detected in 1 subject (17%) after multiple administration of evocalcet 12 mg. In healthy subjects, the tolerability and safety of evocalcet were observed for a single dose of evocalcet at doses up to 20 mg, and for multiple doses up to 12 mg. These results suggest that evocalcet may have a comparable efficacy and better safety profile than that of cinacalcet, one of the current treatments for secondary hyperparathyroidism in patients with chronic kidney disease.
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Head-to-head comparison of the new Calcimimetic Agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism.
Kidney international, 2018Co-Authors: Masafumi Fukagawa, Ryutaro Shimazaki, Tadao AkizawaAbstract:Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new Calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral Calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing Calcimimetics for management of SHPT.
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Etelcalcetide for the treatment of secondary hyperparathyroidism.
Expert opinion on pharmacotherapy, 2017Co-Authors: Naoto Hamano, Hirotaka Komaba, Masafumi FukagawaAbstract:ABSTRACTIntroduction: Calcium sensing receptor is an important target for the treatment of secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is a novel peptide Calcimimetic Agent that has a similar mechanism of action as cinacalcet hydrochloride. Clinical trials of etelcalcetide have been performed in the US, Europe, and Japan, and these trials demonstrated the safety and efficacy of etelcalcetide in dialysis patients. Etelcalcetide has recently been approved in Europe, the US and Japan.Areas covered: We review the development, pharmacokinetics, and clinical efficacy and safety of etelcalcetide for the treatment of SHPT in hemodialysis patients. We also summarize the clinical evidence regarding cinacalcet to forecast the potential clinical benefit of etelcalcetide.Expert opinion: Etelcalcetide is an injectable Calcimimetic with a longer elimination half-life than cinacalcet. The injectable formulation improves adherence and reduces pill burden, while the frequency of gastrointestinal adver...
Kimberly Geoghegan - One of the best experts on this subject based on the ideXlab platform.
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An Investigation into the One-Pot Heck Olefination—Hydrogenation Reaction.
ChemInform, 2011Co-Authors: Kimberly Geoghegan, Susan M. Kelleher, Paul EvansAbstract:The reaction allows a simple and effective access to a number of compounds and can be applied successfully to prepare the Calcimimetic Agent cinacalcet (X).
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An Investigation into the One-Pot Heck Olefination-Hydrogenation Reaction
The Journal of organic chemistry, 2011Co-Authors: Kimberly Geoghegan, Susan M. Kelleher, Paul EvansAbstract:Herein is described an operationally simple process concerning the observation that, following either inter-, or intramolecular Heck olefination, stirring of the so formed substituted alkenyl product under an atmosphere of hydrogen efficiently effects alkene hydrogenation. Overall this two-operation, one-pot “reductive Heck” sequence is notable since direct reductive Heck processes, using additives such as formate salts, are restricted to a limited range of substrates. In total 25 examples are reported (yields ranging from 0 to 95%), which were selected in order to probe the scope and limitations of this method. Finally, the utility of this sequence was demonstrated in a short synthesis of the Calcimimetic Agent, cinacalcet.