Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS).

We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.

Synthesis of Bicyclo[1.1.0]butanes from Iodo-Bicyclo[1.1.1]pentanes.

We describe a two-step process for the synthesis of substituted bicyclo[1.1.0]butanes. A photo-Hunsdiecker reaction generates iodo-bicyclo[1.1.1]pentanes under metal-free conditions at room temperature. These intermediates react with nitrogen and sulfur nucleophiles to afford substituted bicyclo[1.1.0]butane products.

Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy.

Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.

Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.

Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity.

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.

Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro.

Various groups have sought to determine the impact of CYP2C8 genotype (and CYP2C8 inhibition) on the pharmacokinetics (PK) of ibuprofen (IBU) enantiomers. However, the contribution of cytochrome P450 2C8 (CYP2C8) in human liver microsomes (HLMs) has not been reported. Therefore, in vitro cytochrome P450 (P450) reaction phenotyping was conducted with selective inhibitors of cytochrome P450 2C9 (CYP2C9) and CYP2C8. In the presence of HLMs, sulfaphenazole (CYP2C9 inhibitor), and anti-CYP2C9 monoclonal antibodies (mAbs) inhibited (73-100%) the 2- and 3-hydroxylation of both IBU enantiomers (1 and 20 microM). At a higher IBU concentration (500 microM), the same inhibitors were less able to inhibit the 2-hydroxylation of (S)-(+)-IBU (32-52%) and (R)-(-)-IBU (30-64%), whereas the 3-hydroxylation of (S)-(+)-IBU and (R)-(-)-IBU was inhibited 66 to 83 and 70 to 89%, respectively. In contrast, less inhibition was observed with montelukast (CYP2C8 inhibitor, < or =35%) and anti-CYP2C8 mAbs (< or =24%) at all concentrations of IBU. When (S)-(+)-IBU and (R)-(-)-IBU (1 microM) were incubated with a panel of recombinant human P450s, only CYP2C9 formed appreciable amounts of the hydroxy metabolites. At a higher IBU enantiomer concentration (500 microM), additional P450s catalyzed 2-hydroxylation (CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP2B6) and 3-hydroxylation (CYP2C19). When the P450 reaction phenotype and additional clearance pathways are considered (e.g., direct glucuronidation and chiral inversion), it is concluded that CYP2C8 plays a minor role in (R)-(-)-IBU (<10%) and (S)-(+)-IBU ( approximately 13%) clearance. By extension, one would not expect CYP2C8 inhibition (and genotype) to greatly affect the pharmacokinetic profile of either enantiomer. On the other hand, CYP2C9 inhibition and genotype are expected to have an impact on the PK of (S)-(+)-IBU.

Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.