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9. PDB code: 3T9T.
Figure 4. Inhibition of BTK prevents disease in the murine collagen-induced
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arthritis (CIA) model.16
selective irreversible BTK inhibitors. Members of this series show
good efficacy in preclinical in vivo models of RA after oral dosing.
11. The efficiency of covalent inhibitors could be expressed as a function of the
kinact/KI ratio, see Ref. 10 for more detail.
Acknowledgments
KI
E þ I ¢ ½EIꢂ K!inact EIꢃ
The authors thank Eddine Saiah and Suvit Thaisrivongs for sup-
port of the program.
[EI] initial non covalent complex
EI⁄ final covalent complex
Supplementary data
12. Park, H.; Wahl, M. I.; Afar, D. E. H.; Turck, C. W.; Rawlings, D. J.; Tam, C.;
Scharenberg, A. M.; Kinet, J.-P.; Witte, O. N. Immunity 1996, 4, 515.
13. Ellmeier, W.; Jung, S.; Sunshine, M. J.; Hatam, F.; Xu, Y.; Baltimore, D.; Mano,
H.; Littman, D. R. J. Exp. Med. 2000, 192, 1611.
Supplementary data (experimental details for the biological as-
says, BTK autophosphorylation data, mass spectroscopic data of
binding of compound 36 with BTK, and kinase screening data for
compound 36) associated with this article can be found, in the on-
14. The Pfizer institutional animal care and use committee reviewed and approved
the animal use in these studies. The animal care and use program is fully
accredited by the association for assessment and accreditation of laboratory
animal care, international.
15. Lin, T. H.; Hegen, M.; Quadros, E.; Nickerson-Nutter, C. L.; Appell, K. C.; Cole, A.
G.; Shao, Y.; Tam, S.; Ohlmeyer, M.; Wang, B.; Goodwin, D. G.; Kimble, E. F.;
Quintero, J.; Gao, M.; Symanowicz, P.; Wrocklage, C.; Lussier, J.; Schelling, S. H.;
Hewet, A. G.; Xuan, D.; Krykbaev, R.; Togias, J.; Xu, X.; Harrison, R.; Mansour, T.;
Collins, M.; Clark, J. D.; Webb, M. L.; Seidl, K. J. Arthritis Rheum. 2010, 62, 2283.
16. Arthritis was induced by immunizing DBA/1JBomTac mice with bovine type II
collagen (CII) emulsified in complete Freund’s adjuvant and by a boost 21 days
later with CII emulsified in incomplete Freund’s adjuvant, as described
previously.15 Disease severity was evaluated by scoring all four paws for
each animal, with a maximum possible score being 16. 0: No arthritis, 1: One
or two swollen digits, 2: Three or more swollen digits or mild to moderate
swelling of the entire paw, 3: Extensive swelling of the entire paw, 4:
Resolution of swelling, ankylosis of the paw. Values are the mean SEM. Mice
were dosed orally with compound 36 at 0.3, 1, 3, or 10 mg/kg QD. Disease
progression was significantly inhibited by 36 compared to the vehicle control
(P <0.05, by Student’s t-test) at 10 mg/kg (day 7–22), 3 mg/kg (day 5–22) and,
at the end of the study, 1 mg/kg (day 19–22).
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