Structural analysis of the known
NIK inhibitor 3 bound
to the kinase domain of TTBK1 led to the design and synthesis of a
novel class of azaindazole TTBK1 inhibitors exemplified by 8 (cell IC50: 571 nM). Systematic optimization of this
series of analogs led to the discovery of 31, a potent
(cell IC50: 315 nM) and selective TTBK inhibitor with suitable
CNS penetration (rat Kp,uu: 0.32) for in vivo proof of
pharmacology studies. The ability of 31 to inhibit tau
phosphorylation at the disease-relevant Ser 422 epitope was demonstrated
in both a mouse hypothermia and a rat developmental model and provided
evidence that modulation of this target may be relevant in the treatment
of Alzheimer’s disease and other tauopathies.
Structural analysis of a known apoptosis signal-regulating
kinase
1 (ASK1) inhibitor bound to its kinase domain led to the design and
synthesis of the novel macrocyclic inhibitor 8 (cell
IC50 = 1.2 μM). The profile of this compound was
optimized for CNS penetration following two independent strategies:
a rational design approach leading to 19 and a parallel
synthesis approach leading to 26. Both analogs are potent
ASK1 inhibitors in biochemical and cellular assays (19, cell IC50 = 95 nM; 26, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK
assay (19, ER = 5.2; 26, ER = 1.5). In vivo
PK studies revealed that inhibitor 19 had moderate CNS
penetration (K
puu = 0.17) and analog 26 had high CNS penetration (K
puu = 1.0).
Apoptosis
signal-regulating kinase 1 (ASK1) is a key mediator in
the apoptotic and inflammatory cellular stress response. To investigate
the therapeutic value of modulating this pathway in neurological disease,
we have completed medicinal chemistry studies to identify novel CNS-penetrant
ASK1 inhibitors starting from peripherally restricted compounds reported
in the literature. This effort led to the discovery of 21, a novel ASK1 inhibitor with good potency (cell IC50 =
138 nM), low clearance (rat Cl/Clu = 0.36/6.7 L h–1 kg–1) and good CNS penetration (rat K
p,uu = 0.38).
Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor 3. This effort led to the discovery of 32, a potent (cell IC 50 = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Cl u = 1.6/56 L/h/kg and K p,uu = 0.46) for proof-of-pharmacology studies. Specifically, the ability of 32 to inhibit ASK1 in the central nervous system (CNS) was evaluated in a human tau transgenic (Tg4510) mouse model exhibiting elevated brain inflammation. In this study, transgenic animals treated with 32 (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (e.g., IL-1β) in the cortex, thus confirming inhibition of ASK1 in the CNS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.