Page 7 of 8
ACS Medicinal Chemistry Letters
16. Cheng, H.; Bagrodia, S.; Bailey, S.; Edwards, M.; Hoffman, J.;
N-iodosuccinimide; DMF, dimethylformamide; r.t., room
Hu, Q.; Kania, R.; Knighton, D. R.; Marx, M. A.; Ninkovic, S.; Sun,
S.; Zhang, E. Discovery of the highly potent PI3K/mTOR dual
inhibitor PF-04691502 through structure based drug design
MedChemComm 2010, 1 ,139-144.
17. Patel, L.; Chandrasekhar, J.; Evarts, J.; Haran, A. C.; Ip, C.;
Kaplan, J. A.; Kim, M.; Koditek, D.; Lad, L.; Lepist, E.-I.; McGrath,
M. E.; Novikov, N.; Perreault, S.; Puri, K. D.; Somoza, J. R.; Steiner,
B. H.; Stevens, K. L.; Therrien, J.; Treiberg, J.; Villaseñor, A. G.;
Yeung, A.; Phillips, G. 2,4,6-Triaminopyrimidine as a novel hinge
binder in a series of PI3Kδ selective inhibitors J. Med. Chem. 2016,
59, 3532−3548.
1
2
3
4
5
6
7
8
temperature.
REFERENCES
1. Zask, A.; Verheijen,J. C.; Richard, D. J. Recent advances in the
discovery of small-molecule ATP competitive mTOR inhibitors: a
patent review Expert Opin. Ther. Pat.2011, 21, 1109-1127.
2. Roohi, A.; Hojjat-Farsangi, M. Recent advances in targeting
mTOR signaling pathway using small molecule inhibitors J. Drug.
Target. 2017, 25, 189-201.
3. Raychaudhuri, S. K.; Raychaudhuri, S. P. mTOR Signaling
Cascade in Psoriatic Disease: Double Kinase mTOR Inhibitor a Novel
Therapeutic Target Indian J. Dermatol. 2014, 59, 67-70.
4. Huang, T.; Lin, X.; Meng, X.; Lin, M.; Phosphoinositide-3
kinase/protein kinase-B/mammalian target of rapamycin pathway in
psoriasis pathogenesis. A potential therapeutic target? Acta Derm.
Venereol. 2014, 94, 371–379.
5. Wei, K. C.; Lai, P. C.; Combination of everolimus and
tacrolimus: a potentially effective regimen for recalcitrant psoriasis.
Dermatol. Ther. 2015, 28, 25–27.
6. Leo, M. S.; Sivamani, R. K.; Phytochemical modulation of the
Akt/mTOR pathway and its potential use in cutaneous disease. Arch.
Dermatol. Res. 2014, 306, 861–871.
7. Ormerod, A. D.; Shah, S.A.; Copeland, P.; Omar, G.; Winfield,
A. Treatment of psoriasis with topical sirolimus: preclinical
development and a randomized, double-blind trial Br J Dermatol.
2005, 152, 758-764.
8. Agamia, N. F.; Abdallah, D. M.; Sorour, O.; Mourad, B.;
Younan, D. N. Skin expression of mammalian target of rapamycin
and forkhead box transcription factor O1, and serum insulin-like
growth factor-1 in patients with acne vulgaris and their relationship
with diet Br. J. Dermatol. 2016, 174, 1299-1307.
9. Melnik, B. C.; Zouboulis, C. C. Potential role of FoxO1 and
mTORC1 in the pathogenesis of Western diet-induced acne Exp.
Dermatol. 2013, 22, 311-315.
10. For an exhaustive and essential review on topical design see:
Dermal Drug Candidate Selection and Development: An Industrial
Perspective, Trottet, L.; Maibach, H., Eds Springer, 2017.
11. For a recent study highlighting key features to optimize flux
through skin see: Ullrich, T.; Sasmal, S.; Boorgu, V.; Pasagadi, S.;
Cheera, S.; Rajagopalan, S.; Bhumireddy, A.; Shashikumar, D.;
Chelur, S.; Belliappa, C.; Pandit, C.; Krishnamurthy, N.; Mukherjee,
S.; Ramanathan, A.; Ghadiyaram, C.; Ramachandra, M.; Santos, P.
G.; Lagu, B.; Bock, M. G.; Perrone, M.H.; Weiler, S.; Keller, H. 3-
alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor
modulators with ideal physicochemical properties for transdermal
administration J. Med .Chem. 2014, 57, 7396-7411.
12. ChromLogD6.5 was calculated from an HPLC measured
Chromatographic Hydrophobicity Index at pH 6.5 using the following
equation: ChromLogD6.5 = 0.086*CHI6.5 -3.5. pH 6.5 is used to
mimick the more acidic nature of skin. For additional references on
CHI, see: Young, R. J.; Green, D. V. S.; Luscombe, C. N.; Hill, A. P.
Getting physical in drug discovery II: the impact of chromatographic
hydrophobicity Drug Discovery Today 2011, 16, 822-830.
13. For this series of compounds, there was always a significant but
reproducible shift between shake-flask logD7.4 and ChromlogD6.5 that
could not be explained by the pH difference given that the molecules
described in this article are all neutral.
14. Fraser, C.; Carragher, N. O.; Unciti-Broceta, A. eCF309: a
potent, selective and cell-permeable mTOR inhibitor MedChemComm
2016, 7, 471-477.
15. Liu, K. K.-C.; Bagrodia, S.; Bailey, S.; Cheng, H.; Chen, H.;
Gao, L.; Greasley, S.; Hoffman, J. E.; Hu, Q.; Johnson, T. O.;
Knighton, D.; Liu, Z.; Marx, M. A.; Nambu, M. D.; Ninkovic, S.;
Pascual, B.; Rafidi, K.; Rodgers, C. M.-L.; Smith, G. L.; Sun, S.;
Wang, H.; Yang, A.; Yuan, J.; Zou, A. 4-Methylpteridinones as orally
active and selective PI3K/mTOR dual inhibitors Bioorg. Med. Chem
Lett 2010, 20, 6096-6099.
9
18. Barlaam, B.; Cosulich, S.; Fitzek, M.; Germain, H.; Green, S.;
Hanson, L. L.; Harris, C. S.; Hancox, U.; Hudson, K.; Lambert-van
der Brempt, C.; Lamorlette, M.; Magnien, F.; Ouvry, G.; Page, K.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ruston, L.; Ward, L.; Delouvrie, B. Discovery of
a novel
aminopyrazine series as selective PI3K α inhibitors Bioorg. Med.
Chem Lett 2017, 27, 3030-3035.
19. Perreault, S.; Chandrasekhar, J.; Cui, Z.-H.; Evarts, J.; Hao, J.;
Kaplan J. A.; Kashishian, A.; Keegan, K. S.; Kenney, T.; Koditek, D.;
Lad, L.; Lepist, E.-I.; McGrath, M. E.; Patel, L.; Phillips, B.;
Therrien, J.; Treiberg, J.; Yahiaoui, A.; Phillips, G. Discovery of a
phosphoinositide 3‑kinase (PI3K) β/δ inhibitor for the treatment of
phosphatase and tensin homolog (PTEN) deficient tumors: building
PI3Kβ potency in
a PI3Kδ-selective template by targeting
nonconserved Asp856 J. Med. Chem. 2017, 60, 1555−1567.
20. Assay details, complete synthesis schemes and detailed
syntheses of all of the compounds can be found in the supplementary
information.
21. The general kinome scan was done at Eurofins/DiscoverX;
for complete data.
22. PDB codes compound
1 6GVF; compound 3a 6GVG;
compound 3e 6GVH; compound 3j 6GVJ.
23. Yang, H.; Rudge, D. G.; Koos, J. D.; Vaidialingam, B.; Yang,
H. J.; Pavletich, N. P. mTOR kinase structure, mechanism and
regulation Nature, 2013, 497, 217-224.
24. Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.;
Resnati, G.; Terraneo, G. The Halogen Bond Chem. Rev, 2016, 116,
2478–2601.
25. Imai, Y. N.: Inoue, Y.; Nakanishi, I.; Kitaura, K Cl-π
interactions in protein-ligand complexes Protein Sci. 2008, 17, 1129-
1137.
26. Similar halogen-pi interactions have been well characterized in
the Factor Xa inhibitor literature, as exemplified in Perzborn, E.;
Roehrig, S.; Straub, A.; Kubitza, D.; Misselwitz, F. The discovery and
development of rivaroxaban, an oral, direct factor Xa inhibitor Nat.
Rev. Drug. Discov. 2011, 10, 61-75.
27. This halogen displacement has already been documented on
similar heterocycles in Inoue, K.; Ohe, T.; Mori, K.; Sagara, T.; Ishii,
Y.; Chiba, M. Aromatic Substitution Reaction of 2-Chloropyridines
Catalyzed by Microsomal Glutathione S-Transferase 1 Drug Metab.
Dispos. 2009, 37, 1797-1800.
28. One routine test for assessing skin irritancy is the DPRA assay
compound with cysteine and lysine containing peptides.
29. There is significant literature suggesting that the pyrimidone
should be the preferred tautomer in this case: Galvão, T. L.; Rocha, I.
M.; Ribeiro da Silva, M. D.; Ribeiro da Silva, M. A. From 2-
hydroxypyridine to 4(3H)-pyrimidinone: computational study on the
control of the tautomeric equilibrium J. Phys. Chem. A 2013, 117,
12668-12674.
30. Taylor, P. J.; van des Zwan, G.; Antonov, L. Tautomerism:
Introduction, History, and Recent Developments in Experimental and
Theoretical Methods in Tautomerism: Methods and Theories
Antonov, L.; Eds; Wiley-VCH; 2014; pp 1-24.
7
ACS Paragon Plus Environment