Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer’s disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine <b>6</b>, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in <b>24</b> with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency

Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer’s disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine <b>6</b>, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in <b>24</b> with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency

Discovery of Imidazo[1,2‑<i>b</i>]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity

Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo­[1,2-<i>a</i>]­pyrazine <b>10a</b> was identified during an HTS campaign. Although <b>10a</b> exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of <b>10a</b> guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted <b>21b</b> which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo­[1,2-<i>b</i>]­pyridazine-based <b>27f</b>, an extremely potent (cellular Mps1 IC₅₀ = 0.70 nM, A549 IC₅₀ = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This <b>27f</b> demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines

Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine <b>9</b> with an IC₅₀ of 37 nM. The X-ray structure of <b>9</b> revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in <b>9</b>. Further optimization of <b>9</b> led to <b>12</b> with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, <b>12</b> displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity