Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer.

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity.

Analyzing the Potential Root Causes of Variability of Pharmacokinetics in Preclinical Species.

The purpose of this research was to assess variability in pharmacokinetic profiles (PK variability) in preclinical species and identify the risk factors associated with the properties of a drug molecule that contribute to the variability. Exposure data in mouse, rat, dog, and monkey for a total of 16,592 research compounds studied between 1999 and 2013 were included in the analysis. Both in vivo study parameters and in silico/experimental physicochemical properties of the molecules were analyzed.

Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.

Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle.

Inhibition of spleen tyrosine kinase attenuates IgE-mediated airway contraction and mediator release in human precision cut lung slices.

Background And Purpose: Asthma presents as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyper-reactivity (AHR). Spleen tyrosine kinase (Syk) mediates allergen-induced mast cell degranulation, a central component of allergen-induced inflammation and AHR. However, the role of Syk in IgE-mediated constriction of human small airways remains unknown.

Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors.

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa.

Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues.

A new strategy for the synthesis of benzylic sulfonamides: palladium-catalyzed arylation and sulfonamide metathesis.

An efficient two-step strategy has been developed to access diversely functionalized benzylic sulfonamides. Execution of this strategy required the development of two reaction methods: the palladium-catalyzed cross-coupling of aryl halides with CH-acidic methanesulfonamides and a metathesis reaction between the resulting alpha-arylated sulfonamides and diverse amines. The broad scope of the cross-coupling process combined with a versatile sulfonamide metathesis constitutes an efficient strategy for the synthesis of various benzylic sulfonamides.

Two-step synthesis of carbohydrates by selective aldol reactions.

Studies of carbohydrates have been hampered by the lack of chemical strategies for the expeditious construction and coupling of differentially protected monosaccharides. Here, a synthetic route based on aldol coupling of three aldehydes is presented for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by l-proline, is then followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid.

The first direct and enantioselective cross-aldol reaction of aldehydes.

The first enantioselective catalytic direct cross-aldol reaction that employs nonequivalent aldehydes has been accomplished using proline as the reaction catalyst. Structural variation in both the aldol donor (R1 = Me, n-Bu, Bn, 91 to >99%) and aldol acceptor (R2 = I-Pr, I-Bu, c-C6H11, Et, Ph, 97-99% ee) are possible while maintaining high reaction efficiency (75-88% yield). Significantly, this new aldol variant allows facile enantioselective access to a broad range of beta-hydroxy aldehydes which are valuable intermediates in polyketide syntheses.

The first general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones.

The first general approach to enantioselective catalysis of the Diels-Alder reaction with simple ketone dienophiles has been accomplished. The use of iminium catalysis has enabled enantioselective access to a fundamental Diels-Alder reaction variant that has previously been unavailable using chiral Lewis acid catalysis. A new chiral amine catalyst has been developed that allows a variety of monodentate cyclic and acyclic ketones to successfully participate in enantioselective [4 + 2] cycloadditions.