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Supplementary Figure 4 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 7 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 1 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 4 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 7 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 2 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 5 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 8 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 9 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 6 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 6 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 2 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure Legends from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 5 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 3 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 1 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Data Supplement from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Table 3 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Supplementary Figure 10 from Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC50 values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. Mol Cancer Ther; 9(8); 2344–53. ©2010 AACR.

Supplementary Table 1 from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

Supplementary Table 2 from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck's effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.

Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.

[Image: see text] Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

This Letter describes the development of a convergent, efficient route to the CHK1 inhibitor MK-8776. This synthetic approach relies upon the cyclization of a bispyrazole adduct 10 with a optically pure β-keto nitrile 9 to construct the pyrazolo[1,5-a]pyrimidine scaffold in a single step.

A novel class of 5-amino-2,5-dideoxy-2,2-difluorocytidine derivatives has been synthesized in order to identify anticancer nucleoside analogs. Several synthetic routes were devised and implemented which relied upon either SN2 displacement or reductive amination to provide the desired derivatives.

The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan-Pim inhibitors such as 11j are described.

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.

Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

The CXC chemokine receptor 2 (CXCR2) has attracted a considerable amount of attention as a target for therapeutic intervention due the key role this receptor plays in a number of inflammatory disorders. Over the past decade, several classes of potent, selective CXCR2 receptor antagonists have been developed as potential anti-inflammatory agents. These small-molecule chemokine receptor antagonists have demonstrated the ability to inhibit CXCR2-mediated recruitment of inflammatory cells in-vitro as well as shown efficacy in-vivo in various animal models of inflammation. In addition, several of the most advanced CXCR2 receptor antagonists have recently demonstrated promising proof-of-activity results in early human clinical trials. This review details the discovery and development of the 3,4-diaminocyclobut-3-ene-1,2-dione-based CXCR2 receptor antagonist class including SCH 527123 which is currently in mid-stage clinical evaluation. The medicinal chemistry efforts leading to the discovery of SCH 527123, the in-vitro and in-vivo pharmacology for this compound, and an overview of the clinical evaluation of SCH 527123 will also be discussed.

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.

CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.

In neutrophils, growth-related protein-alpha (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42:2874-2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [(3)H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.

Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.

A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.

A series of 5′-amino derivatives of gemcitabine are synthesized in order to identify anticancer nucleoside analogues (no biological activity reported).

A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as alpha side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.

Enantiomerically pure cis -2,4-disubstituted piperidines were synthesized from chiral thiolactam 2 in six steps via a highly diastereoselective homoenolate alkylation which set the stereochemistry at the C4 carbon. In addition, two cleavage methods were used to cleave the lactam to the desired piperidines with a high level of diastereoselection at the newly created C2 stereocenter.

Enantiomerically pure vinylcyclopropanes were synthesized from selective palladium-catalyzed and copper-mediated S N 2′ nucleophilic reactions of chiral cyclopropyl lactones.