Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424 via an Organocatalytic Aza-Michael Reaction

Lin, Qiuxia; Meloni, David; Pan, Yongchun; Xia, Michael; Rodgers, James D.; Shepard, Stacey; Li, Mei; Galya, Laurine; Metcalf, Brian W.; Yue, Tai‐Yuen; Liu, Pingli; Zhou, Jiacheng

doi:10.1021/ol900350k

Cited by 150 publications

(81 citation statements)

References 25 publications

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“…In an effort to evaluate the therapeutic potential of JAK inhibition in MPNs, we identified INCB018424, 22 a potent and selective inhibitor of JAK1 and JAK2 with IC 50 values of 3.3nM and 2.8nM, respectively (Table 1). INCB018424 demonstrated modest selectivity against Tyk2 (ϳ 6-fold) and marked selectivity (Ն 130-fold) against JAK3.…”

Section: Identification and Biochemical Characterization Of Incb018424mentioning

confidence: 99%

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Quintás‐Cardama

Vaddi

Liu

et al. 2010

Blood

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722

580

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Section: Identification and Biochemical Characterization Of Incb018424mentioning

confidence: 99%

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Quintás‐Cardama

Vaddi

Liu

et al. 2010

Blood

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722

580

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“…In addition, JAK2 plays a central role in the signal transduction of erythropoietin and thrombopoietin (Neubauer et al, 1998;Parganas et al, 1998) and has been shown to play a critical role in erythropoiesis and thrombopoiesis in humans. [3][4]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424) is an orally active and potent inhibitor of JAKs with greater than 100-fold selectivity against a panel of 26 non-JAK kinases and is in development for the treatment of myeloproliferative neoplasms (Lin et al, 2009;Quintás-Cardama et al, 2010). INCB018424 has demonstrated efficacy in myelofibrosis, the most serious of the chronic myeloproliferative neoplasms for which there is no approved therapy (Verstovsek et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Metabolism, Excretion, and Pharmacokinetics of [¹⁴C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

Shilling

Nedza²,

Emm³

et al. 2010

Drug Metab Dispos

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102

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ABSTRACT:The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [ 14 C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t 1/2 of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono-and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.

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“…Based on previous literature [14], a synthetic strategy was successfully set, starting from commercially available 4-hydroxy-proline leading to the desired organocatalyst in good overall yield (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Multi-step enzyme-organocatalyst C–C bond forming reactions in deep-eutectic-solvents: towards improved performances by organocatalyst design

Müller

Rosen

Marı́a

2015

Sustain Chem Process

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Background: Deep eutectic solvents (DES) have recently emerged as promising non-hazardous environmentallyfriendly solvents. In this respect, the use of DES as media for multi-step enzyme-organocatalysis (C-C bond formation via aldol-type reactions) represents a promising sustainable option. Being soluble in DES, organocatalysts may be retained in the DES phase during biphasic extractive work-up (e.g. with biogenic 2-methyl-tetrahydrofuran), enabling product recovery and organocatalyst recycling within the DES phase simultaneously.Main results: Herein, the proof-of-concept of designing organocatalysts-sspecifically tailored for DES-that may be properly retained in the DES phase (immobilized) among extractive cycles is demonstrated for the first time. To this end, the incorporation of novel hydrogen-bond donor groups (e.g. −OH) in the organocatalyst structure appears as a promising option to achieve improved results, leading to 1.5-fold higher conversions and yields, together with excellent chemoselectivities (>90%) for the new organocatalyst. Reactions are conducted using different bio-based DES, showing the broad applicability and possibilities that these processes may have. Conclusions and implications:In this work it is demonstrated that organocatalysts can be tuned to be used in different DES. This first proof-of-concept may trigger new research and applications of DES as sustainable solvents for enantioselective C-C bond forming reactions, whereby the organocatalyst design can play an important role for optimized integrated process set-up.

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Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424 via an Organocatalytic Aza-Michael Reaction

Cited by 150 publications

References 25 publications

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Metabolism, Excretion, and Pharmacokinetics of [¹⁴C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

Multi-step enzyme-organocatalyst C–C bond forming reactions in deep-eutectic-solvents: towards improved performances by organocatalyst design

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Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424 via an Organocatalytic Aza-Michael Reaction

Cited by 150 publications

References 25 publications

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

Multi-step enzyme-organocatalyst C–C bond forming reactions in deep-eutectic-solvents: towards improved performances by organocatalyst design

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Metabolism, Excretion, and Pharmacokinetics of [¹⁴C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans