LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

This letter describes the structure-activity relationship (SAR) of the 'right-wing' alpha-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing alpha-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved. (C) 2010 Elsevier Ltd. All rights reserved.

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Proc Amer Assoc Cancer Res, Volume 47, 2006 4726 SNS-595 is a novel naphthyridine analog that acts specifically during the S-phase to induce rapid apoptosis of cells that are actively synthesizing DNA, resulting in cell cycle arrest in the G2 phase. SNS-595 is being developed for the treatment of both solid and hematologic malignancies. Current treatment of relapsed or refractory acute leukemias and advanced chronic myelogenous leukemia remains suboptimal. In patients with acute myelogenous leukemia (AML), failure to achieve a complete remission (CR) after induction chemotherapy or relapse occurring within the first year after diagnosis is associated with a poor prognosis. In patients with accelerated or blast-phase chronic myelogenous leukemia (CML) the response rates to intensive chemotherapy regimens are less than 30%, and in responding patients the median remission duration averages 4 to 6 months. SNS-595 has potent anti-proliferative effects on human leukemic cell lines in vitro. IC50 values, determined by MTT assay in four human promyelocytic, and acute lymphoblastic leukemia cell lines, range from 40 to 170 nM. Intravenous administration of SNS-595 to nu/nu mice with LM-3 Jck hematologic xenograft tumors resulted in 97 to 99% tumor growth inhibition. All mice treated with SNS-595 had significant reductions in tumor volume, with a complete response rate of 67%. Similarly, SNS-595 also showed 98% tumor growth inhibition in mice bearing CCRF-CEM xenograft tumors. The effect of IV administered SNS-595 on bone-marrow cellularity and circulating levels of leukocytes in CD-1 mice was measured after drug administration on days 0 and 4. Two days after the second administration of SNS-595, bone marrow isolated from femurs showed a dose-dependent reduction in cellularity. At 20 mg/kg, cellularity was reduced to 7.5%, while circulating neutrophils were reduced from a pre-dose level of 1244 ±55 cells/μL to a nadir of 51 ±24 cells/μL blood on day 8. Absolute neutrophil counts subsequently rebounded and soon returned to normal levels. Total WBCs also reached a nadir on day 8, but returned to normal levels. In conclusion, in vitro and in vivo data show that SNS-595 has potent anti-proliferative activity on human leukemic cell lines, inhibits tumor growth in hematologic xenografts, and reversibly ablates murine bone marrow cells. These data suggest that SNS-595 has the potential to demonstrate important clinical activity in patients with hematologic malignancies.

Proc Amer Assoc Cancer Res, Volume 46, 20052293 Although recent research has identified cancer therapies with non-cytotoxic mechanisms, there is still a need to discover and develop the next generation of cytotoxics with strong activities, manageable toxicities, and novel mechanisms of action. SNS-595 is a first-in-class naphthyridine compound that demonstrates potent cytotoxic activity as well as robust antineoplastic activity in several syngeneic and human xenograft tumor models, and is currently in phase I clinical trials for solid tumors. In vitro, SNS-595 has been observed to induce G2 cell cycle arrest and subsequent apoptosis in various cancer cells, including many multi-drug resistant lines. The effect of SNS-595 on cell cycle progression and checkpoint stimulation has been characterized and compared to the effects of a number of therapeutically relevant cell cycle modulators (cisplatin, docetaxol, gemcitabine, etoposide, doxorubicin, irinotecan, bleomycin, and mitomycin C). Cell cycle progression was analyzed using both DNA content and the cell cycle markers cyclins A, B, and E. In asynchronous populations, SNS-595 treatment causeed a full G2 arrest in all cell lines tested. This arrest was accompanied by rapid apoptosis as determined by DNA fragmentation. In synchronized cell populations treated with SNS-595, cells cycled normally until they reached S phase, which was 30% longer than in untreated cells. Checkpoint markers (chk kinases, cdc25 phosphatases, cdc2, and p21) appeared rapidly upon entering S phase, and the cells eventually reached a sustained and irreversible arrest with 4N DNA content. SNS-595 is shown to be distinct from the other G2 arrestors tested in that it causes p21 expression early in S phase and a significant S-phase lag. SNS-595 is also differentiable from other S-phase active compounds in showing a definitive arrest at G2 as opposed to a varied G1/S/G2 arrest profile. Further research into the stimulation of checkpoint and apoptotic pathways by SNS-595 will lead to a more detailed understanding of this compound’s potent anticancer activity.