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Drugs of the Future: Pacritinib

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Drugs of the Future: Pacritinib DRUGS OF THE FUTURE VOLUME 38 NUMBER 6 JUNE 2013 +1 800 336 4474 + +34 934 592 220 L A +81 3 5218 6500 F IP & SCIENCE - DOF38-6_Pacritinib_Verstovsek_Drugs_of_the_Future_2013 27/06/2013 9:10 Page 375 Drugs of the Future 2013, 38(6): 375-386 copyright © 2013 Prous Science, S.A.U. or its licensors. All rights reserved. ccc: 0377-8282/2013 Doi: 10.1358/dof.2013.38.6.1964716 MonoGRAPH PAcRitinib Inhibitor of Tyrosine-Protein Kinase JAK2 Prop inn Inhibitor of FLT-3 Treatment of Myelofibrosis Sb-1518 11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8(26),9,11,16,21,23-decaene inchi: 1S/c28H32n4o3/c1-2-13-32(12-1)14-17-35-27-9-8-25-19-24(27)21-34-16-4-3-15-33-20-22-6-5-7-23(18-22)26-10-11-29-28(30-25)31- 26/h3-11,18-19H,1-2,12-17,20-21H2,(H,29,30,31)/b4-3+ antitumor efficacy. Pharmacokinetic studies in humans have con- firmed that pacritinib has adequate oral bioavailability and predictable pharmacokinetics, supporting clinical development. In phase I and II O clinical studies, pacritinib was well tolerated, with mild to moderate, manageable gastrointestinal toxicity as the most common adverse event. Clinical activity has been demonstrated in both MPNs and non- O Hodgkin’s lymphoma. Phase III development in primary and secondary O (post-essential thrombocythemia or post-polycythemia vera) myelofi- N N brosis is ongoing. NN Key words: Myelofibrosis – Acute myeloid leukemia – tyrosine- H protein kinase inhibitor – Pacritinib – Sb-1518 SYNTHESIS c28H32n4o3 Pacritinib can be prepared by two closely related ways: Mol wt: 472.5787 1) O-Alkylation of 5-nitrosalicylaldehyde (i) with 1,2-dichloroethane cAS: 937272-79-2 (iia) (1, 2) or 1-bromo-2-chloroethane (iib) (3) by means of K2co3 in En: 453356 DMF at 100-5 °c (1) or 60 °c (3) affords 2-(2-chloroethoxy)-5- nitrobenzaldehyde (iii), which by reduction with nabH4 in tHF (1) or MeoH (3) yields the corresponding alcohol (iV). O-Alkylation of alco- SUMMARY hol (iV) with allyl bromide (V) and KoH and bu4nHSo4 (1) or bu4ni at 40 °c (3) gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitroben- Tyrosine-protein kinase JAK2 inhibitors are a promising new therapy zene (Vi), which is then reduced with Fe in the presence of nH4cl in for the treatment of myeloproliferative neoplasms (MPNs). Pacritinib EtoH to yield the corresponding aniline (Vii). condensation of amine (SB-1518) is a novel macrocyclic compound that combines selective (Vii) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (Viii) by inhibition of JAK2 and receptor-type tyrosine-protein kinase FLT3, and means of Hcl in buoH at 80 °c affords the 2-anilinopyrimidine offers potential for the treatment of MPNs and FLT3-dependent disor- derivative (iX), which then undergoes ring-closing metathesis in the ders such as acute myeloid leukemia. Through targeted inhibition, presence of Grubbs’ second-generation catalyst and Hcl in cH cl interference in the STAT signaling pathway, and induction of apoptosis 2 2 at 40-45 °c to yield macrocycle (X). Finally, compound (X) is submit- and cell growth arrest, pacritinib has selective activity on JAK2- and ted to microwave-assisted condensation with pyrrolidine (Xi) in FLT3-dependent cell lines. Preclinical data support pacritinib’s dimethylacetamide at 80 °c (1-3). Scheme 1. intermediate (Viii) can be prepared by Suzuki coupling of 2,4-di - chloropyrimidine (Xii) with 3-(hydroxymethyl)phenylboronic acid (Xiii) in the presence of Pd(oAc) , PPh and na co in tHF at 70 °c S. Verstovsek1, c. Machida2, J.P. Dean2 and H. Myint2. 1Leukemia Department, Unit 428, 2 3 2 3 MD Anderson cancer center, 1515 Holcombe blvd., Houston, texas 77030, USA; 2cell (1) or Pd(PPh3)4 and na2co3 in DME at 80-5 °c (3) to give [3-(2- therapeutics, inc., 3101 Western Ave. #600, Seattle, Washington 98121, USA. E-mail: chloropyrimidin-4-yl)phenyl]methanol (XiV), which is finally O-alkyl - [email protected]. *Synthesis prepared by J. bolòs, R. castañer. thomson Reuters, Provença 398, 08025 ated with allyl bromide (V) and KoH and bu4nHSo4 or cs2co3 in barcelona, Spain. DMF at 40 °c (1-3). Scheme 1. 375 DOF38-6_Pacritinib_Verstovsek_Drugs_of_the_Future_2013 27/06/2013 9:10 Page 376 PAcRitinib S. Verstovsek et al. Scheme 1. Synthesis of Pacritinib H O H O OH K CO NaBH OH 2 3 O 4 O Cl Cl O N R O N O N 2 Cl 2 2 (I) (III) (IV) (II a R=Cl) (II b R=Br) CH2 KOH, Bu4NHSO4 or Bu4NI OH Br (V) CH2 B(OH)2 OH (XIII) Cl O N Pd(OAc) , PPh , Na CO N 2 3 2 3 O or Pd(PPh3)4, Na2CO3 N Cl Cl N Cl (XII) O2N (XIV) (VI) CH Br 2 (V) CH O 2 Fe, NH4Cl KOH, Bu4NHSO4 or Cs2CO3 CH2 N CH2 O CH2 N Cl (VIII) O O HCl O Cl O N Cl H2N N N H (VII) (IX) Grubbs 2nd-generation catalyst, HCl HN O O (XI) O O O O N Cl N N N N N N H H (X) 376 tHoMSon REUtERS – Drugs of the Future 2013, 38(6) DOF38-6_Pacritinib_Verstovsek_Drugs_of_the_Future_2013 27/06/2013 9:10 Page 377 S. Verstovsek et al. PAcRitinib 2) condensation of 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitro - tecture and constitutional symptoms secondary to increased levels benzene (Vi) with pyrrolidine (Xi) in dimethylacetamide at 60 °c of proinflammatory cytokines (5). When assessed by different prog- affords 1-[2-[2-(allyloxymethyl)-4-nitrophenoxy]ethyl]pyrrolidine nostic factors, survival estimates for MF patients range from < 2 (Xii), which by reduction with Sncl2 in MeoH/cH2cl2 (1) or with Fe years to > 10 years (6). Allogeneic hematopoietic stem cell trans- and nH4cl (2) provides the corresponding aniline (Xiii). coupling of plant remains the only curative therapy, but many patients are not amine (Xiii) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine eligible for this treatment due to advanced age or comorbidity sta- (Viii) in the presence of Hcl in buoH at 100 °c gives the diallyl deriv- tus. All other current MF treatments target symptom alleviation, ative (XiV), which finally undergoes ring-closing metathesis in the reduction of splenomegaly or improvement in anemia, and include presence of Grubbs’ second-generation catalyst and tFA in cH2cl2 hydroxyurea, splenectomy, splenic/hepatic radiation, blood and/or at 50 °c (1) or in the presence of the Zhan-1b catalyst (2). Scheme 2. platelet transfusion, erythropoiesis-stimulating agents and other immunomodulatory or antiinflammatory therapies (7). BACKGROUND A specific mutation in the tyrosine-protein kinase JAK2, JAK2V617F, Myeloproliferative neoplasms (MPns) are a group of diseases includ- has been identified in almost all patients with PV and in approxi- ing polycythemia vera (PV), essential thrombocythemia (Et) and pri- mately half of the patients with Et and PMF (8). the mutation is in mary myelofibrosis (PMF) (4). MF may present as a primary diagno- the pseudokinase domain of the JAK2 molecule, eliminating the sis (PMF) or develop from essential thrombocythemia (PEt-MF) or inhibitory effect of the pseudokinase on the kinase part of the mole- polycythemia vera (PPV-MF). Symptoms and signs of MF include cule, and leading to an overactive JAK2–StAt pathway. Additional anemia, splenomegaly, fibrotic remodeling of bone marrow archi- data suggest that in patients without JAK2V617F, other mutations Scheme 2. Synthesis of Pacritinib CH2 CH2 CH2 O O SnCl2 or O Fe, NH4Cl O O O Cl N N HN O2N O2N H2N (VI) (XII) (XIII) (XI) CH O 2 HCl N N Cl (VIII) CH2 O O CH2 O Grubbs 2nd-generation catalyst, TFA O or Zhan-1B catalyst O N N O N N N N H N N H (XIV) tHoMSon REUtERS – Drugs of the Future 2013, 38(6) 377 DOF38-6_Pacritinib_Verstovsek_Drugs_of_the_Future_2013 27/06/2013 9:10 Page 378 PAcRitinib S. Verstovsek et al. and abnormalities in JAK2-dependent cell signaling are often pres- Since StAt proteins are phosphorylated and activated by JAKs, the ent, and this signaling is critical for MPn pathogenesis, progression, finding of frequent StAt activation in AML suggests a role for persistence and symptomatology in these patients. in essence, dys- increased JAK2–StAt signaling (possibly due to alterations in JAK2 regulation of the JAK2–StAt pathway underlies aberrant biological regulatory proteins) in the pathogenesis of AML that could be mod- processes in all patients with MPns. ified by JAK2 inhibition. Similarly, while JAK2 mutations typically do not occur in solid tumors, preclinical data have demonstrated initial clinical studies of JAK2 inhibitors show promising activity in abnormal JAK2–StAt signaling that responds to JAK2 inhibition in treating MPns, and to date, this activity does not significantly differ a variety of cancers (21). the effects of JAK2 inhibition at the cell in MF patients harboring the JAK2V617F mutation as compared to level have been studied in brain tumors (22), breast cancer (23) and those who do not have the mutation (9). Ruxolitinib is a JAK1 and other solid tumors (21). clinical studies investigating the potential JAK2 inhibitor which was recently approved worldwide for the treat- antitumor activity of JAK2 inhibitors in these cancer types are there- ment of patients with intermediate- or high-risk MF. Approval was fore of interest. based on data from the phase iii studies, coMFoRt i and ii, which included a significant reduction in splenomegaly and improvement in MF-related constitutional symptoms. Hematological effects, PRECLINICAL PHARMACOLOGY including anemia and thrombocytopenia, were notable toxicities Pacritinib has been tested in vitro for inhibitory activity against > 50 and resulted in dose modifications, dose interruptions and blood protein kinases that constitute a representative cross-section of the product transfusions (10, 11).
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