The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

The development of a stereospecific synthesis of a IDO1-selective inhibitor is described. The synthetic strategy toward enabling early discovery efforts along with additional findings pertaining to process safety that limited scalability are outlined. A convergent approach that supported the synthesis of material suitable for early preclinical and/or good laboratory practice toxicology studies and avoided the formation of key high-energy intermediates is summarized.

Inhibitors of PI3Kdelta are approved as monotherapy for the treatment of hematologic malignancies such as follicular B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Recent reports suggest that inhibition of PI3Kdelta in mice is effective against solid cancers as well. Mechanistic studies by several groups have suggested a possible adaptive immune-mediated anti-tumor response involving immunosuppressive Tregs and/or MDSCs in the tumor microenvironment. Our structure-guided discovery program led to the identification of a novel heterocycloalkyl purine inhibitor class with excellent isoform and kinome selectivity, as well as good solubility. Optimization included potency enhancements, addressing metabolism and increasing half-life in preclinical species to provide a PI3Kdelta inhibitor with a low once-daily predicted human dose. In FoxP3 reporter mice harboring MC38 tumors treated with inhibitor, we observed reduced peripheral Treg function and an increased ratio of CD8 to Treg in both spleen and tumor-infiltrating lymphocytes. In three-week efficacy studies, modest tumor growth inhibition was found in 4T1, MC38 and CT26 syngeneic tumor models when our inhibitor was dosed as a single agent and we demonstrated a trend towards better efficacy when our inhibitor was dosed in combination with an anti-mPD-1 antibody in CT26 tumor-bearing mice as compared to anti-mPD-1 alone. These preliminary studies confirm the impact of PI3Kdelta inhibition on T-cell subpopulations, and support continued exploration of PI3Kdelta inhibitors for the treatment of solid tumors, either as monotherapy or in combination with other agents.Citation Format: Joey L. Methot, Hua Zhou, Meredith A. McGowan, Benjamin W. Trotter, Michael Altman, Xavier Fradera, Charles Lesburg, Chaomin Li, Stephen Alves, Craig P. Chappell, Renu Jain, Ruban Mangado, Elaine Pinheiro, Sybil M. Williams, Peter Goldenblatt, Armetta D. Hill, Lynsey Shaffer, Dapeng Chen, Robbie L. McLeod, Hyun-Hee Lee, Sanjiv Shah, Jason D. Katz. Solid tumor activity with a selective PI3Kdelta inhibitor as a single agent and in combination with anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2254.

A versatile synthesis of dihydropyridobenzodiazepines that proceeds via a palladium-catalyzed C-N coupling and catalytic hydrogenation cascade is reported. The intermediate 2-anilinonicotinaldehydes may be efficiently protected to ultimately afford N6 differentiated dihydropyridobenzodiazepines, which facilitates further elaboration.

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

A two-step C—N coupling/cyclization reaction sequence is developed for the synthesis of imidazopyridine derivatives.

IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat.

La presente invention concerne des purines 2,6,7,8-substituees ou un sel pharmaceutiquement acceptable de ces composes. Les composes representatifs sont utiles en tant qu'inhibiteurs de la proteine HDM2. L'invention concerne egalement des compositions pharmaceutiques comprenant lesdits composes et des methodes potentielles de traitement du cancer utilisant celles-ci.

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. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.

Alzheimer’s disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.