Long-Acting Tumor-Activated Prodrug of a TGFßR Inhibitor.

Inhibition of TGFß signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFß receptor (TGFßR) inhibitors in cancer therapy. To restrict the activity of TGFßR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFßR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.

Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists.

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9).

The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

Pyrrolo[1,2-f]triazines as JAK2 inhibitors: achieving potency and selectivity for JAK2 over JAK3.

SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.

Benzo[d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)--Hit to Lead studies.

Hit to Lead optimization and SAR development led to the identification of the potent and selective benzo[d]imidazole inhibitor (17b) of Co-activator Associated Arginine Methyltransferase (CARM1).

Core exploration in optimization of chemokine receptor CCR4 antagonists.

The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg).

Optimization of CCR4 antagonists: side-chain exploration.

The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED(50) 30 mg/kg).

Identification of chemokine receptor CCR4 antagonist.

The present study reports the identification and hits to leads optimization of chemokine receptor CCR4 antagonists. Compound 12 is a high affinity, non-cytotoxic antagonist of CCR4 that blocks the functional activity mediated by the receptor.

Identification of a potent and rapidly reversible inhibitor of the 20S-proteasome.

Synthesis and in vitro characterization of novel, lactam boronic acid based, selective, and rapidly reversible inhibitor 14 of the 20S-proteasome is presented.

Chiral nonracemic alpha-alkylidene and alpha-silylidene cyclopentenones from chiral allenes using an intramolecular allenic Pauson-Khand-type cycloaddition.

We have successfully effected a transfer of chirality from a chiral nonracemic allene to an alpha-alkylidene and an alpha-silylidene cyclopentenone. The molybdenum-mediated examples possessing a silyl group on the terminus of the allene show good facial selectivities, but isomerization of the (E)-silylidene cyclopentenone to the (Z)-silylidene cyclopentenone occurs upon purification of these products. Alternatively, an alkyl group on the terminus of the allene undergoes cycloaddition with moderate selectivities but gives products that undergo an isomerization of the (Z)-alkylidene cyclopentenone to the (E)-alkylidene cyclopentenone when exposed to acidic conditions. Thus, erosion of the enantiomeric excesses is observed for one of the two products as a result of this isomerization. The allenic Pauson-Khand-type cycloaddition has also been effected by first isolation the (eta(6)-arene)molybdenum tricarbonyl complex, demonstrating for the first time that this is most likely the active complex in the molybdenum-mediated reactions. Attempts to increase the facial selectivity by increasing the size of the arene moiety resulted in a marginal increase in the selectivity at the expense of the yield. Based upon these results, we have concluded that altering the approach for the preparation of nonracemic alpha-alkylidene cyclopentenones is necessary in order to obtain synthetically useful levels of stereocontrol.