3 research outputs found
Carbamoyl Pyridone HIV‑1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
We report herein the discovery of
the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors
dolutegravir (S/GSK1349572) (<b>3</b>) and S/GSK1265744 (<b>4</b>). These drugs stem from a series of carbamoyl pyridone analogues
designed using a two-metal chelation model of the integrase catalytic
active site. Structure–activity studies evolved a tricyclic
series of carbamoyl pyridines that demonstrated properties indicative
of once-daily dosing and superior potency against resistant viral
strains. An inherent hemiaminal ring fusion stereocenter within the
tricyclic carbamoyl pyridone scaffold led to a critical substrate
controlled diastereoselective synthetic strategy whereby chiral information
from small readily available amino alcohols was employed to control
relative and absolute stereochemistry of the final drug candidates.
Modest to extremely high levels of stereochemical control were observed
depending on ring size and position of the stereocenter. This approach
resulted in the discovery of <b>3</b> and <b>4</b>, which
are currently in clinical development
Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)
Monopolar spindle 1 (Mps1) is essential
for centrosome duplication, the spindle assembly check point, and
the maintenance of chromosomal instability. Mps1 is highly expressed
in cancer cells, and its expression levels correlate with the histological
grades of cancers. Thus, selective Mps1 inhibitors offer an attractive
opportunity for the development of novel cancer therapies. To design
novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone
(<b>4</b>, SP600125) and its crystal structure bound to JNK1.
Our design efforts led to the identification of indazole-based lead <b>6</b> with an Mps1 IC<sub>50</sub> value of 498 nM. Optimization
of the 3- and 6-positions on the indazole core of <b>6</b> resulted
in <b>23c</b> with improved Mps1 activity (IC<sub>50</sub> =
3.06 nM). Finally, application of structure-based design using the
X-ray structure of <b>23d</b> bound to Mps1 culminated in the
discovery of <b>32a</b> and <b>32b</b> with improved potency
for cellular Mps1 and A549 lung cancer cells. Moreover, <b>32a</b> and <b>32b</b> exhibited reasonable selectivities over 120
and 166 kinases, respectively
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 IC<sub>50</sub> 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