7 research outputs found
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol
This
work describes the optimization and scale-up of a Buchwald–Hartwig
amination reaction for the preparation of a pharmaceutical intermediate.
This C–N bond formation is challenged by the use of a chiral
primary amine, which both adds cost and favors formation of biaryl
byproducts. In order to develop a scalable process, a number of factors
had to be investigated including catalyst selection and stoichiometry
of the chiral amine. These all needed to be optimized while maintaining
low palladium levels in the isolated product. The reaction was found
to be most effective using PdÂ(dba)<sub>2</sub> with BINAP and Cs<sub>2</sub>CO<sub>3</sub> in THF. When executed on 2.5 kg scale, these
conditions provided 2.06 kg of the desired product in 80% yield with
only 73 ppm residual palladium. To date, this process has been successfully
executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>
Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Chemical
probes are required for preclinical target validation
to interrogate novel biological targets and pathways. Selective inhibitors
of the CREB binding protein (CREBBP)/EP300 bromodomains are required
to facilitate the elucidation of biology associated with these important
epigenetic targets. Medicinal chemistry optimization that paid particular
attention to physiochemical properties delivered chemical probes with
desirable potency, selectivity, and permeability attributes. An important
feature of the optimization process was the successful application
of rational structure-based drug design to address bromodomain selectivity
issues (particularly against the structurally related BRD4 protein)
Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication
A series of CCR5 antagonists representing the thiophene-3-yl-methyl
ureas were designed that met the pharmacological criteria for HIV-1
inhibition and mitigated a human ether-a-go-go related gene (hERG)
inhibition liability. Reducing lipophilicity was the main design criteria
used to identify compounds that did not inhibit the hERG channel,
but subtle structural modifications were also important. Interestingly,
within this series, compounds with low hERG inhibition prolonged the
action potential duration (APD) in dog Purkinje fibers, suggesting
a mixed effect on cardiac ion channels
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1‑((2<i>S</i>,5<i>R</i>)‑5-((7<i>H</i>‑Pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)Âamino)-2-methylpiperidin-1-yl)Âprop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans
Significant
work has been dedicated to the discovery of JAK kinase
inhibitors resulting in several compounds entering clinical development
and two FDA approved NMEs. However, despite significant effort during
the past 2 decades, identification of highly selective JAK3 inhibitors
has eluded the scientific community. A significant effort within our
research organization has resulted in the identification of the first
orally active JAK3 specific inhibitor, which achieves JAK isoform
specificity through covalent interaction with a unique JAK3 residue
Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme
presented a unique challenge in the design of covalent inhibitors
with appropriate pharmacodynamics properties coupled with limited
unwanted off-target reactivity. This effort resulted in the identification
of <b>11</b> (PF-06651600), a potent and low clearance compound
with demonstrated in vivo efficacy. The favorable efficacy and safety
profile of this JAK3-specific inhibitor <b>11</b> led to its
evaluation in several human clinical studies
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1‑((2<i>S</i>,5<i>R</i>)‑5-((7<i>H</i>‑Pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)Âamino)-2-methylpiperidin-1-yl)Âprop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans
Significant
work has been dedicated to the discovery of JAK kinase
inhibitors resulting in several compounds entering clinical development
and two FDA approved NMEs. However, despite significant effort during
the past 2 decades, identification of highly selective JAK3 inhibitors
has eluded the scientific community. A significant effort within our
research organization has resulted in the identification of the first
orally active JAK3 specific inhibitor, which achieves JAK isoform
specificity through covalent interaction with a unique JAK3 residue
Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme
presented a unique challenge in the design of covalent inhibitors
with appropriate pharmacodynamics properties coupled with limited
unwanted off-target reactivity. This effort resulted in the identification
of <b>11</b> (PF-06651600), a potent and low clearance compound
with demonstrated in vivo efficacy. The favorable efficacy and safety
profile of this JAK3-specific inhibitor <b>11</b> led to its
evaluation in several human clinical studies
Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV‑1 Replication
The
redesign of the previously reported thiophene-3-yl-methyl urea
series, as a result of potential cardiotoxicity, was successfully
accomplished, resulting in the identification of a novel potent series
of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold.
The main redesign criteria were to reduce the number of rotatable
bonds and to maintain an acceptable lipophilicity to mitigate hERG
inhibition. The structure–activity relationship (SAR) that
was developed was used to identify compounds with the best pharmacological
profile to inhibit HIV-1. As a result, five advanced compounds, <b>6d</b>, <b>6e</b>, <b>6i</b>, <b>6h</b>, and <b>6k</b>, were further evaluated for receptor selectivity, antiviral
activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro
and in vivo safety. On the basis of these results, <b>6d</b> and <b>6h</b> were selected for further development
Identification of <i>N</i>‑{<i>cis</i>-3-[Methyl(7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases
Janus kinases (JAKs)
are intracellular tyrosine kinases that mediate
the signaling of numerous cytokines and growth factors involved in
the regulation of immunity, inflammation, and hematopoiesis. As JAK1
pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would
be expected to inhibit many cytokines involved in inflammation and
immune function while avoiding inhibition of the JAK2 homodimer regulating
erythropoietin and thrombopoietin signaling. Our efforts began with
tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid
arthritis. Through modification of the 3-aminopiperidine linker in
tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar
potency in a human whole blood assay. Improvements in JAK1 potency
and selectivity were achieved via structural modifications suggested
by X-ray crystallographic analysis. After demonstrating efficacy in
a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (<b>25</b>) was nominated as a clinical candidate for the treatment
of JAK1-mediated autoimmune diseases