Current and emerging therapies for Achondroplasia: The dawn of precision medicine.

Achondroplasia is a rare disease affecting bone growth and is caused by a missense mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. In the past few years, there were multiple experimental drugs entering into clinical trials for treating achondroplasia including vosoritide, the first precision medicine approved for this indication. This perspective presents the mechanism of action, benefit, and potential mechanistic limitation of the drugs currently being evaluated in clinical trials for achondroplasia. This article also discusses the potential impact of those drugs not only in increasing the growth of individuals living with achondroplasia but also in improving their quality of life.

Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression.

Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

Cyclic amide bioisosterism: strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.

Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.

Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors.

A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.

Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors.

A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.

Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity.

The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by α-synuclein (α-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson's disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against α-syn-mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced α-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson's disease and other synucleinopathies.

Palladium-catalyzed, heteroatom assisted, regioselective cyclizations.

Unusual Pd-catalyzed cyclizations of unsymmetrical allylic acetates, where the nucleophile is tethered to the central allyl carbon, are shown for the first time to be remarkably controlled by heteroatom-mediated preassociation of the reacting partners.

Small-molecule inhibitors of spleen tyrosine kinase as therapeutic agents for immune disorders: will promise meet expectations?

Following on the heels of the US FDA approval of tofacitinib (Xeljanz, Pfizer, USA), an inhibitor of the JAK family members, and ibrutinib (Imbruvica, Janssen, Belgium), an inhibitor of BTK, for the treatment of rheumatoid arthritis and chronic lymphocytic leukemia, respectively, there is now renewed interest in the biopharmaceutical industry in the development of orally active small-molecule agents targeting key protein kinases implicated in immune regulation. One such 'immunokinase' target is SYK, a non-receptor tyrosine protein kinase critical for transducing intracellular signaling cascades for various immune recognition receptors, such as the B-cell receptor and the Fc receptor. Here, we review and discuss the progress and challenges in the development of small-molecule inhibitors of SYK and their potential as a new class of disease-modifying immunosuppressive agents for certain inflammatory and autoimmune disorders.

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.

Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives.

Spleen Tyrosine Kinase (SYK) and Bruton's Tyrosine Kinase (BTK) are non-receptor cytoplasmic tyrosine kinases that are primarily expressed in cells of hematopoietic lineage. Both are key mediators in coupling activated immunoreceptors to downstream signaling events that affect diverse biological functions, from cellular proliferation, differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological inhibitors of SYK or BTK are being actively pursued as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders. Deregulation of SYK or BTK activity has also been implicated in certain hematological malignancies. To date, from a clinical perspective, pharmacological inhibition of SYK activity has demonstrated encouraging efficacy in patients with rheumatoid arthritis (RA), while patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have benefited from covalent inhibitors of BTK in early clinical studies. Here, we review and discuss recent insights into the emerging role of the SYK-BTK axis in innate immune cell function as well as in the maintenance of survival and homing signals for tumor cell progression. The current progress on the clinical development of SYK and BTK inhibitors is also highlighted.

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.

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.

Potent and highly selective benzimidazole inhibitors of PI3-kinase delta.

Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.

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, ß, 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, ß, 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.