Journal of Medicinal Chemistry
Featured Article
Mirzadegan, T.; Rabinowitz, M. H.; Shankley, N. P. Pharmacological
characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimida-
zol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and
selective hypoxia-inducible factor prolyl hydroxylase inhibitor. Mol.
Pharmacol. 2011, 79, 910−920. (b) Rosen, M. D.; Venkatesan, H.;
Peltier, H. M.; Bembenek, S. D.; Kanelakis, K. C.; Zhao, L. X.;
Leonard, B. E.; Hocutt, F. M.; Wu, X.; Palomino, H. L.; Brondstetter,
T. I.; Haugh, P. V.; Cagnon, L.; Yan, W.; Liotta, L. A.; Young, A.;
Mirzadegan, T.; Shankley, N. P.; Barrett, T. D.; Rabinowitz, M. H.;
Benzimidazole-2-pyrazole, H. I. F. Prolyl 4-Hydroxylase Inhibitors as
Oral Erythropoietin Secretagogues. ACS Med. Chem. Lett. 2010, 1,
526−529.
(10) For exceptional reviews, see (a) Chowdhury, R.; Hardy, A.;
Schofield, C. J. The human oxygen sensing machinery and its
manipulation. Chem. Soc. Rev. 2008, 37, 1308−1319. (b) Yan, L;
Colandrea, V. J.; Hale, J. J. Prolyl hydroxylase domaincontaining
protein inhibitors as stabilizers of hypoxia-inducible factor: small
molecule-based therapeutics for anemia. Expert Opin. Ther. Pat. 2010,
20, 1219−1245. (c) Rabinowitz, M. H.; Barrett, T. D.; Rosen, M. D.;
Venkatesan, H. Inhibitors of HIF prolyl hydroxylases. Annu. Rep. Med.
Chem. 2010, 45, 23−139. (d) Muchnik, E.; Kaplan, J. HIF prolyl
hydroxylase inhibitors for anemia. Expert Opin. Invest. Drugs 2011, 20,
645−656.
(11) (a) Hewitson, K. S.; Schofield, C. J.; Ratcliffe, P. J. Hypoxia-
inducible factor prolyl-hydroxylase: purification and assays of PHD2.
Methods Enzym. 2007, 435, 25−42. (b) McDonough, M. A.; Li, V.;
Flashman, E.; Chowdhury, R.; Mohr, C.; Lienard, B. M. R.; Zondlo, J.;
Oldham, N. J.; Clifton, I. J.; Lewis, J.; McNeill, L. A.; Kurzeja, R. J. M.;
Hewitson, K. S.; Yang, E.; Jordan, S.; Syed, R. S.; Schofield, C. J.
Cellular oxygen sensing: crystal structure of hypoxia-inducible factor
prolyl hydroxylase (PHD2). Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
9814−9819.
(12) Annis, D. A.; Athanasopoulos, J.; Curran, P. J.; Felsch, J. S.;
Kalghatgi, K.; Lee, W. H.; Nash, H. M.; Orminati, J. P. A.; Rosner, K.
E.; Shipps, G. W.; Thaddupathy, G. R. A.; Tyler, A. N.; Vilenchik, L.;
Wagner, C. R.; Wintner, E. A. An affinity selection−mass spectrometry
method for the identification of small molecule ligands from self-
encoded combinatorial libraries. Discovery of a novel antagonist of E.
coli dihydrofolate reductase. Int. J. Mass Spectrom. 2004, 238, 77−83.
(13) For a detailed description of bioassays, refer to the Experimental
Section and Supporting Information.
ABBREVIATIONS USED
■
PHD, prolyl hydroxylase; AS-MS, affinity selection mass
spectrometry; HT, high-throughput; HTE, high-throughput
experimentation; PK, pharmacokinetics; Kv11.1, potassium
̀
channel gene; hERG, human ether-a-go-go related gene;
ALT, alanine aminotransferese; EPO, erythropoietin; RBC,
red blood cell; CKD, chronic kidney disease; CIA, chemo-
therapy-induced anemia; ACD, anemia of chronic disease; iv,
intravenous; HIF, hypoxia-inducible factor; FIH, factor
inhibiting hypoxia-inducible factor; PD, pharmacodynamic;
SAR, structure−activity relationship; MOPED, mouse pharma-
codynamic erythropoietin determination; POC, proof-of-
concept; TMHD, 1,1,6,6-tetramethyl-3,5-heptadione; MED,
minimal efficacious dose; NOEL, no observable effect level;
PPB, plasma protein binding; LMs, liver microsomes; AE,
adverse effect; NMP, N-methymorpholine; DMF, N,N-
dimethylformamide; LiHMDS, lithium bis(trimethylsilyl)-
amide; DME, dimethoxyethane; PXR, pregnane X receptor;
CYP, cytochrome P450; Cav1.2, calcium channel 1.2; PPB,
plasma−protein binding; VEGF, vascular endothelial growth
factor; RP, reversed phase; HPLC, high-pressure liquid
chromatography
REFERENCES
■
(1) (a) Vilayur, E.; Harris, D. C. H. Emerging therapies for chronic
kidney disease: what is their role? Nature Rev. Nephrol. 2009, 5, 375−
383. (b) Kuro-o, M. Klotho in chronic kidney diseaseWhat’s new?
Nephrol., Dial., Transplant. 2009, 24, 1705−1708.
(2) Littlewood, T. J.; Collins, G. P. Pharmacotherapy of anemia in
cancer patients. Expert Rev. Clin. Pharm. 2008, 1, 307−317.
(3) (a) Cavill, I.; Auerbach, M.; Bailie, G. R.; Barrett-Lee, P.; Beguin,
Y.; Kaltwasser, P.; Littlewood, T.; Macdougall, I. C.; Wilson, K. Iron
and the anaemia of chronic disease: a review and strategic
recommendations. Curr. Med. Res. Opin. 2006, 22, 731−737.
(b) Weiss, G.; Goodnough, L. T. Anemia of chronic disease. N.
Engl. J. Med. 2005, 352, 1011−1023. (c) Minamishima, Y. K.; Kaelin,
W. G. Jr. Reactivation of Hepatic EPO Synthesis in Mice After PHD
Loss. Science 2010, 329, 407.
(4) (a) Percy, M. J.; Zhao, Q.; Flores, A.; Harrison, C.; Lappin, T. R.
J.; Maxwell, P. H.; McMullin, M. F.; Lee, F. S. A family with
erythrocytosis establishes a role for prolyl hydroxylase domain protein
2 in oxygen homeostasis. Proc. Natl Acad. Sci. U.S.A. 2006, 103, 654−
659. (b) Minamishima, Y. A.; Moslehi, J.; Bardeesy, N.; Cullen, D.;
Bronson, R. T.; Kaelin, W. G. Jr. Somatic inactivation of the PHD2
prolyl hydroxylase causes polycythemia and congestive heart failure.
Blood 2008, 111, 3236−3244.
(5) Chang, Z. Y.; Chiang, C. H.; Lu, D.-W.; Yeh, M.-K.
Erythropoiesis-stimulating protein delivery in providing erythropoiesis
and neuroprotection. Expert Opin. Drug Delivery 2008, 5, 1313−1321.
(6) Cornes, P.; Coiffier, B.; Zambrowski, J.-J. Erythropoietic therapy
for the treatment of anemia in patients with cancer: a valuable clinical
and economic option. Curr. Med. Res. Opin. 2007, 23, 357−368.
(7) (a) Boulahbel, H.; Duran, R. V.; Gottlieb, E. Prolyl hydroxylases
as regulators of cell metabolism. Biochem. Soc. Trans. 2009, 37, 291−
294. (b) Rocha, S. Gene regulation under low oxygen: holding your
breath for transcription. Trends Biochem. Sci. 2007, 32, 389−397.
(8) (a) Provenzano, R. FG-2216, A Novel Oral HIF-PHI, Stimulates
Erythropoiesis and Increases Hemoglobin Concentration in Patients
with Non-Dialysis CKD. National Kidney Foundation Spring Clinical
Meetings 08, Dallas, TX,April 3−6, 2008, Abstract 120. (b) Persons,
D. A. A pill for some anemias? Blood 2007, 110, 1709.
(14) Clements, M. J.; Debenham, J. S.; Walsh, T.; Hale, J. J.
Unpublished; manuscript in preparation.
(15) While introduction of the hydroxypyrimidine substituent
certainly played a role in the enhancement of the PK properties of
4f, it remains unclear whether a secondary interaction of the
hydroxypyrimidine substituent with the enzyme might have con-
tributed to the observed PD enhancement. It is noteworthy however,
that in silico modeling of the enzyme interaction with 4f vs 5
suggested orthogonal binding modes with respect to the hydroxypyr-
imidine subunit.
(16) Initial conditions for this transformation used for the first
synthesis of 6a were analogous to step b1 in Scheme of Table 1: ArI,
CuI, MeNHCH2CH2NHMe, dioxane.
(17) (a) Berritt, S.; Goble, S. D.; Tudge, M. T.; Conway, D.; Dreher,
S. D. Minimizing the cost of organic chemistry experimentation: low-
barrier microscale high-throughput experimentation. 240th ACS
National Meeting, Boston, MA, August 22−26, 2010, ORGN-1054.
(b) Dreher, S. D. Low-barrier high-throughput experimentation tools
for efficient chemistry development. 240th ACS National Meeting,
Boston, MA, August 22−26, 2010, ORGN-522. (c) Vachal, P.; Sun, Y.
Merck catalysis needs for drug discovery, development, and
commercialization. 242nd ACS National Meeting, Denver, CO,
August 28−September 1, 2011, ORGN-2.
(18) Several N-alkyl, N-acyl, and urea derivatives of 6 were prepared.
While many exhibited promising in vitro binding, none proved
efficacious in vivo and the PK profile was generally suboptimal.
(19) Mass Spectrometer: Micromass ZQ single quadrupole, electro-
spray positive ionization, full scan mode (150−750 amu in 0.5s).
(9) Another example of small molecule PHDi preclinical effort has
been recently disclosed: (a) Barrett, T. D.; Palomino, H. L.;
Brondstetter, T. I.; Kanelakis, K. C.; Wu, X.; Haug, P. V.; Yan, W.;
Young, A.; Hua, H.; Hart, J. C.; Tran, D.-T.; Venkatesan, H.; Rosen,
M. D.; Peltier, H. M.; Sepassi, K.; Rizzolio, M. C.; Bembenek, S. D.;
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dx.doi.org/10.1021/jm201542d | J. Med. Chem. 2012, 55, 2945−2959