IKKP inhibitors

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Fig. 30 In vitro potency, log D and permeability of a series of imidazolo[l,2-h]pyridazine-based IKKp inhibitors...

The advantageous impact of fluorine on permeabihty has been explored in the discovery of a family of imidazolo[l,2-fc]pyridazine-based IKKp inhibitors where it was assumed that the central benzamide played a key role in pharmacokinetic properties [127], As shown in Fig. 30, modifications to the benzamide region (C-3) of the imidazo[l,2-fc]pyridazine had a dramatic affect on permeability the measured PAMPA values for 79 and 80 were 0.84x10 cm/s and 19x10 cm/s, respectively [ 128]. Although 79 and 80 differ by only a single F-for-H substitution, the observed improvement in permeabihty is presumed to arise from a combination of factors. These factors include the enhancement of hydrophobicity and the formation of a weak interaction between the fluorine atom and the NH moiety, possibly a dipolar interaction. 

Shimizu H, Yamasaki T, Yoneda Y, Muro F, Hamada T, Yasukochi T, Tanaka S, Told T, Yokoyama M, Morishita K, limura S (2011) Discovery of imidazo[l,2-l>]pyridazines as IKKp inhibitors. Part 3 Exploration of effective compounds in arthritis models. Biooig Med Chem Lett 21 4550-4555 and refs therein... 

Kaneko S, Sato K, Shikanai D, Yamada R, Sakurada K (2010) Preparation of 8-substituted isoquinoUne derivatives as IKKp kinase inhibitors. Patent W02010038465 (Al), 8 Apr 2010... 

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