3 research outputs found
Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors
The discovery and optimization of a series of 6,7-dihydro-5<i>H</i>-cyclopentaÂ[<i>d</i>]Âpyrimidine compounds that
are ATP-competitive, selective inhibitors of protein kinase B/Akt
is reported. The initial design and optimization was guided by the
use of X-ray structures of inhibitors in complex with Akt1 and the
closely related protein kinase A. The resulting compounds demonstrate
potent inhibition of all three Akt isoforms in biochemical assays
and poor inhibition of other members of the cAMP-dependent protein
kinase/protein kinase G/protein kinase C extended family and block
the phosphorylation of multiple downstream targets of Akt in human
cancer cell lines. Biological studies with one such compound, <b>28</b> (GDC-0068), demonstrate good oral exposure resulting in
dose-dependent pharmacodynamic effects on downstream biomarkers and
a robust antitumor response in xenograft models in which the phosphatidylinositol
3-kinase–Akt–mammalian target of rapamycin pathway is
activated. <b>28</b> is currently being evaluated in human clinical
trials for the treatment of cancer
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]ÂtriazoloÂ[4,3-<i>a</i>]Âpyridin-3-yl)Âmethanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain