6 research outputs found
Rational Design of Highly Selective Spleen Tyrosine Kinase Inhibitors
A novel approach to design selective spleen tyrosine
kinase (Syk)
inhibitors is described. Inhibition of spleen tyrosine kinase has
attracted much attention as a mechanism for the treatment of autoimmune
diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib,
a Syk inhibitor that successfully completed phase II clinical trials,
also exhibits some undesirable side effects. More selective Syk inhibitors
could offer safer, alternative treatments. Through a systematic evaluation
of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding
site as a rare combination among sequence aligned kinases and hypothesized
that optimizing the interaction between them and a Syk inhibitor molecule
would impart high selectivity for Syk over other kinases. We report
the structure-guided identification of three series of selective spleen
tyrosine kinase inhibitors that support our hypothesis and offer useful
guidance to other researchers in the field
Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors
Inhibition
of spleen tyrosine kinase has attracted much attention
as a mechanism for the treatment of cancers and autoimmune diseases
such as asthma, rheumatoid arthritis, and systemic lupus erythematous.
We report the structure-guided optimization of pyridazine amide spleen
tyrosine kinase inhibitors. Early representatives of this scaffold
were highly potent and selective but mutagenic in an Ames assay. An
approach that led to the successful identification of nonmutagenic
examples, as well as further optimization to compounds with reduced
cardiovascular liabilities is described. Select pharmacokinetic and
in vivo efficacy data are presented
Novel Series of Dihydropyridinone P2X7 Receptor Antagonists
Identification of singleton P2X7
inhibitor <b>1</b> from
HTS gave a pharmacophore that eventually turned into potential clinical
candidates <b>17</b> and <b>19</b>. During development,
a number of issues were successfully addressed, such as metabolic
stability, plasma stability, GSH adduct formation, and aniline mutagenicity.
Thus, careful modification of the molecule, such as conversion of
the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper
substitution at C-5″, and in some cases addition of fluorine
atoms to the aniline ring allowed for the identification of a novel
class of potent P2X7 inhibitors suitable for evaluating the role of
P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders
Novel Series of Dihydropyridinone P2X7 Receptor Antagonists
Identification of singleton P2X7
inhibitor <b>1</b> from
HTS gave a pharmacophore that eventually turned into potential clinical
candidates <b>17</b> and <b>19</b>. During development,
a number of issues were successfully addressed, such as metabolic
stability, plasma stability, GSH adduct formation, and aniline mutagenicity.
Thus, careful modification of the molecule, such as conversion of
the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper
substitution at C-5″, and in some cases addition of fluorine
atoms to the aniline ring allowed for the identification of a novel
class of potent P2X7 inhibitors suitable for evaluating the role of
P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders
Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors
We describe the discovery of several pyrrolopyrazines
as potent and selective Syk inhibitors and the efforts that eventually
led to the desired improvements in physicochemical properties and
human whole blood potencies. Ultimately, our mouse model revealed
unexpected toxicity that precluded us from further advancing this
series
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IA(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization