ACS Medicinal Chemistry Letters
Letter
Arylboronic acids and pinacol esters used to make 1, 3, 4, 6, 19, and
21 are commercially available. Arylboronic acids to make 515 and 816
are derived from the corresponding arylbromides, which are prepared
according to the corresponding references. Compound 4 was con-
verted to the acid chloride with (COCl)2, then reduced to 2 with NaBH4.
Intermediates to make compounds containing Cp-CF3 groups were
prepared according to Scheme 2.
(5) Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla,
I.; Schuler, F.; Rogers-Evans, M.; Muller, K. Oxetanes in drug
discovery: structural and synthetic insights. J. Med. Chem. 2010, 53 (8),
3227−3246.
(6) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
Marki, M.; Godel, T.; Fischer, H.; Wagner, G.; Parrilla, I.; Schuler, F.;
Schneider, J.; Alker, A.; Schweizer, W. B.; Muller, K.; Carreira, E. M.
Spirocyclic oxetanes: synthesis and properties. Angew. Chem., Int. Ed.
2008, 47 (24), 4512−4515.
(7) Wuitschik, G.; Carreira, E. M.; Rogers-Evans, M.; Muller, K.
Oxetan-3-one: chemistry and synthesis. Process Chem. Pharm. Ind.
2008, 217−229.
a
Scheme 2. Synthesis of Cp-CF3-Containing Aryl Bromides
(8) Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Fischer, H.; Wagner,
B.; Schuler, F.; Polonnchuk, L.; Carreira, E. M. Oxetanes as promising
modules in drug discovery. Angew. Chem., Int. Ed. 2006, 45 (46),
7736−7739.
(9) In vitro potency comparisons have been published for
compounds containing either tert-butyl or Cp-CF3 (refs 9−11). To
the best of our knowledge, there are no reports of using the Cp-CF3
group to increase metabolic stability compared to tert-butyl: Paone, D.
V.; Nguyen, D. N.; Shaw, A. W.; Burgey, C. S.; Potteiger, C. M.; Deng,
J. Z.; Mosser, S. D.; Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.;
Selnick, H. G.; Vacca, J. P.; Williams, T. M. Orally bioavailable
imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor
antagonists: Discovery of MK-2918. Bioorg. Med. Chem. Lett. 2011, 21
(9), 2683−2686.
a
Reagents and conditions: (a) X = CH, MsCl, 18-crown-6, KF, DMF,
100 °C;17 X = N: Tebbe reagent;18 (b) CH2N2;19 (c) Xylenes reflux19.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral characterization data.
This material is available free of charge via the Internet at
(10) Lee, S. H.; Seo, H. J.; Lee, S.-H.; Jung, M. E.; Park, J.-H.; Park,
H.-J.; Yoo, J.; Yun, H.; Na, J.; Kang, S. Y.; Song, K.-S.; Kim, M.-a.;
Chang, C.-H.; Kim, J.; Lee, J. Biarylpyrazolyl oxadiazole as potent,
selective, orally bioavailable cannabinoid-1 receptor antagonists for the
treatment of obesity. J. Med. Chem. 2008, 51 (22), 7216−7233.
(11) Phillips, D. J.; Davenport, R. J.; Demaude, T. A.; Galleway, F. P.;
Jones, M. W.; Knerr, L.; Perry, B. G.; Ratcliffe, A. J. Imidazopyridines
as VLA-4 integrin antagonists . Bioorg. Med. Chem. Lett. 2008, 18 (14),
4146−4149.
AUTHOR INFORMATION
■
Corresponding Author
Notes
The authors declare no competing financial interest.
(12) Lundahl, A.; Lennernas, H.; Knutson, L.; Bondesson, U.;
̈
Hedeland, M. Identification of finasteride metabolites in human bile
and urine by high-performance liquid chromatography/tandem mass
spectrometry. Drug Metab. Dispos. 2009, 37 (10), 2008.
ACKNOWLEDGMENTS
■
We thank Phong Nguyen for performing CYP reaction
phenotyping and for helpful discussion. We further acknowl-
edge George Marsh, Myrtha Durena, Melissa Queliz, and Jaimie
Spear for performing in vivo experiments and Danuta Lubicka
for formulating compounds for in vivo dosing. We further
acknowledge Shari Bickford and Jenny Zhan for performing
reversible and time-dependent CYP inhibition experiments. We
thank Stephane Rodde for performing LogP determinations.
(13) Hulin-Curtis, S. L.; Petit, D.; Figg, W. D.; Hsing, A. W.;
Reichardt, J. K. V. Finasteride metabolism and pharmacogenetics: new
approaches to personalized prevention of prostate cancer. Future
Oncol. 2010, 6 (12), 1897.
(14) For an example, where a site other than tert-butyl was the
primary site of metabolism, replacing the tert-butyl with Cp-CF3 did
not improve clearance: Guo, C.; McAlpine, I.; Zhang, J.; Knighton, D.
D.; Kephart, S.; Johnson, M. C.; Li, H.; Bouzida, D.; Yang, A.; Dong,
L.; Marakovits, J.; Tikhe, J.; Richardson, P.; Guo, L. C.; Kania, R.;
Edwards, M. P.; Kraynov, E.; Christensen, J.; Piraino, J.; Lee, J.;
Dagostino, E.; Del-Carmen, C.; Deng, Y.-L.; Smeal, T.; Murray, B. W.
Discovery of pyrroloaminopyrazoles as novel PAK inhibitors. J. Med.
Chem. 2012, 55 (10), 4728−4739.
(15) Brodney, M. A. Pyridyl piperazines and Their Preparation and
Pharmaceutical Compositions, for the Treatment of CNS Disorders or
Conditions That Can Be Treated by Serotonin-Mediated Neuro-
transmission. PCT Int. Appl., 2006000912, 2006.
(16) Gandon, V.; Bertus, P.; Szymoniak, J. A straightforward
synthesis of cyclopropanes from aldehydes and ketones. Eur. J. Org.
Chem. 2000, 22, 3713−3719.
(17) Nader, B. S.; Cordova, J. A.; Reese, K. E.; Powell, C. L. A Novel
Fluoride Ion Mediated Olefination of Electron-Deficient Aryl Ketones
by Alkanesulfonyl Halides. J. Org. Chem. 1994, 59 (10), 2898−2901.
(18) Phillion, D. P.; Cleary, D. G. Disodium salt of 2-
[(dihydroxyphosphinyl)difluoromethyl]propenoic acid: an isopolar
and isosteric analog of phosphoenolpyruvate. J. Org. Chem. 1992, 57
(9), 2763−2764.
(19) Banks, B. J. Preparation of 1-aryl-4-cyclopropylpyrazoles as
medical and agrochemical parasiticides and pesticides. EP 0933363,
1999. Safety note: diazomethane is an explosion hazard.
ABBREVIATIONS
■
CpCF3, trifluoromethylcyclopropyl; Cl, clearance; Cyps, cytochrome
P450s; HLM, human liver microsomes; RLM, rat liver microsomes;
SPhos, dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine;
t1/2, half-life; Vss, volume of distribution
REFERENCES
■
(1) Lau, Y. Y.; Krishna, G.; Yumibe, N. P.; Grotz, D. E.; Sapidou, E.;
Norton, L.; Chu, I.; Chen, C.; Soares, A. D.; Lin, C. C. The use of in
vitro metabolic stability for rapid selection of compounds in early
discovery based on their expected hepatic extraction ratios. Pharm. Res.
2002, 19 (11), 1606−1610.
(2) Obach, R. S. Prediction of human clearance of twenty-nine drugs
from hepatic microsomal intrinsic clearance data: an examination of in
vitro half-life approach and nonspecific binding to microsomes. Drug
Metab. Dispos. 1999, 27 (11), 1350−1359.
(3) Guengerich, F. P. Cytochrome P450 and Chemical Toxicology.
Chem. Res. Toxicol. 2008, 21 (1), 70−83.
(4) Lu, A. Y.; Wang, R. W.; Lin, J. H. Cytochrome P450 in vitro
reaction phenotyping: A re-evaluation of approaches used for P450
isoform identification. Drug Metab. Dispos. 2003, 31 (4), 345−350.
C
dx.doi.org/10.1021/ml400045j | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX