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Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases.

ABSTRACT: Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1-acetonaphthone yielded an enantiopure (R)-amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)-alcohol, which was easily converted into the previous (R)-amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co-immobilized on the same porous surface. This self-sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA-based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

SUBMITTER: Marx L

PROVIDER: S-EPMC6001662 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases.

Marx Lisa L Ríos-Lombardía Nicolás N Farnberger Judith F JF Kroutil Wolfgang W Benítez-Mateos Ana I AI López-Gallego Fernando F Morís Francisco F González-Sabín Javier J Berglund Per P

Advanced synthesis & catalysis 20180228 11

Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1-acetonaphthone yielded an enantiopure (<i>R</i>)-amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (<i>S</i>)-alcohol, which wa ...[more]

PMID: 29937706

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Project description:Rationale & objectiveSome US hemodialysis (HD) facilities switched from oral cinacalcet to intravenous etelcalcetide as the primary calcimimetic therapy to control parathyroid hormone (PTH) levels after the introduction of etelcalcetide in 2017. Although clinical trials have demonstrated the superior efficacy of etelcalcetide versus cinacalcet, evidence comparing real-world effectiveness is lacking.Study designProspective cohort.Setting & participantsPatients receiving HD enrolled in US Dialysis Outcomes and Practice Patterns Study facilities.ExposureWe classified HD facilities on the basis of whether >75% of calcimimetic users were prescribed etelcalcetide ("etelcalcetide-first") or cinacalcet ("cinacalcet-first") from March-August 2019.OutcomesPTH, calcium, and phosphorus levels among calcimimetic users, all averaged in the 6 months after the exposure assessment period.Analytical approachWe used adjusted linear regression to compare outcomes using 2 approaches: (1) cross-sectional comparison of etelcalcetide-first and cinacalcet-first HD facilities; (2) pre-post comparison of HD facilities that switched from cinacalcet-first to etelcalcetide-first using facilities that remained cinacalcet-first as a comparison group.ResultsWe identified 45 etelcalcetide-first and 67 cinacalcet-first HD facilities; etelcalcetide-first (vs cinacalcet-first) facilities were more likely to be from small or independent dialysis organizations (86% vs 22%) and had higher total calcimimetic use (43% vs 29%) and lower active vitamin D use (66% vs 82%). In the cross-sectional analysis comparing etelcalcetide-first and cinacalcet-first HD facilities, the adjusted mean difference in PTH levels was -115 pg/mL (95% CI, -196 to -34) and the prevalence of a PTH level of >600 pg/mL was lower (prevalence difference, -11.4%; 95% CI, -19.3% to -3.5%). Among facilities that switched to etelcalcetide-first, the mean PTH level decreased from 671 to 484 pg/mL and the prevalence of a PTH level of >600 pg/mL decreased from 39% to 21%. Among facilities that remained cinacalcet-first, the mean PTH level increased from 632 to 698 pg/mL and the prevalence of a PTH level of >600 pg/mL increased from 37% to 43%. The adjusted difference-in-difference between the switch to etelcalcetide-first and the continuation of cinacalcet-first was -169 pg/mL (-249 to -90 pg/mL) for the mean PTH and -14.4% (-22.0% to -6.8%) for a PTH level of >600 pg/mL. We also observed slightly lower serum calcium levels and minimal differences in serum phosphorus levels between the etelcalcetide-first and the cinacalcet-first facilities.LimitationsResidual confounding.ConclusionsWe observed better PTH control in HD facilities that switched from using cinacalcet to etelcalcetide as the primary calcimimetic therapy. Further research is needed to investigate how the greater real-world effectiveness of intravenous etelcalcetide (vs oral cinacalcet) may affect clinical outcomes.

Dataset Information

Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases.

Publications

Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases.

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