7 research outputs found
Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate
Herein, the route
scouting and early process development of a key
cyclopentylpyrimidine ketone intermediate toward the synthesis of
Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate
were prepared through a method that commenced with the natural product
(<i>R</i>)-(+)-pulegone and relied on the early construction
of a methyl-substituted cyclopentyl ring system. The first process
chemistry route, detailed herein, enabled the synthesis of the ketone
on a hundred-gram scale, but it was not feasible for the requisite
production of multikilogram quantities of this compound and necessitated
the exploration of alternative strategies. Several new synthetic approaches
were investigated towards the preparation of the cyclopentylpyrimidine
ketone, in either racemic or chiral form, which resulted in the discovery
of a more practical route that hinged on the initial preparation of
a highly substituted dihydroxypyrimidine compound. The cyclopentane
ring in the target was then constructed through a key carbonylative
esterification and subsequent tandem Dieckmann cyclization–decarboxylation
sequence that was demonstrated in a racemic synthesis. This proof-of-concept
was later developed into an asymmetric synthesis of the cyclopentylpyrimidine
ketone, which will be described in a subsequent paper, along with
the synthesis of Ipatasertib
Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats
Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species
A hallmark of Alzheimer\u27s disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer\u27s disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey. © 2013 American Chemical Society
A Phase I/II Trial of Cetuximab in Combination with Interleukin-12 Administered to Patients with Unresectable Primary or Recurrent Head and Neck Squamous Cell Carcinoma
Discovery of a Novel Class of Imidazo[1,2‑<i>a</i>]Pyridines with Potent PDGFR Activity and Oral Bioavailability
The
in silico construction of a PDGFRβ kinase homology model
and ensuing medicinal chemistry guided by molecular modeling, led
to the identification of potent, small molecule inhibitors of PDGFR.
Subsequent exploration of structure–activity relationships
(SAR) led to the incorporation of a constrained secondary amine to
enhance selectivity. Further refinements led to the integration of
a fluorine substituted piperidine, which resulted in significant reduction
of P-glycoprotein (Pgp) mediated efflux and improved bioavailability.
Compound <b>28</b> displayed oral exposure in rodents and had
a pronounced effect in a pharmacokinetic–pharmacodynamic (PKPD)
assay
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