Daniel Jon Sall

1,2-Disubstituted indole, azaindole and benzimidazole derivatives possessing amine moiety : A novel series of thrombin inhibitors

A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.

Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling

The Hedgehog (Hh) pathway is a highly conserved signaling system that plays an important role in embryonic development and tissue homeostasis through regulation of cell differentiation and proliferation, and deregulated Hh signaling has been implicated in variety of cancers. Two distinct mechanisms are responsible for inappropriate and uncontrolled Hh pathway activation in human malignancies: ligand-dependent, due to over-expression of Hh ligand, and ligand-independent, resulting from genetic mutations in pathway components such as Patched (Ptch) and Smoothened (Smo). Smo, a member of the class F G-protein coupled receptor family, is a key regulator of Hh signaling pathway, and therefore is an attractive target for pathway modulation. We have identified a potent and selective small molecule antagonist of Smo. This novel molecule (LY2940680) binds to the Smo receptor and potently inhibits Hh signaling in Daoy, a human medulloblastoma tumor cell line, and C3H10T½, a mouse mesenchymal cell line. Importantly, LY2940680 binds to and inhibits the functional activity of resistant Smo mutant (D473H) produced by treatment with GDC-0449 (a Smo antagonist from Genentech). LY2940680 also has excellent pharmacokinetic properties in rodent and non-rodent species. Treatment of Ptch +/− p53 −/− transgenic mice, which spontaneously develop medulloblastoma, with oral administration of LY2940680 produced remarkable efficacy and significantly improved their survival. Magnetic resonance imaging of these mice revealed rapid kinetics of anti-tumor activity. Immunohistochemistry analysis of medulloblastoma tumors showed that LY2940680 treatment induced Caspase-3 activity and reduced proliferation. LY2940680 inhibited Hh regulated gene expression in the subcutaneous xenograft tumor stroma and produced significant anti-tumor activity. In summary, we have characterized an orally bio-available small molecule Smo antagonist that may provide therapeutic benefit to cancer patients with deregulated Hh signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2819. doi:10.1158/1538-7445.AM2011-2819

Chapter 11. Future Antithrombotic Therapy

Publisher Summary This chapter summarizes the recent advancement in the synthesis and characterization of select agents that hold the promise of being future antithrombotic therapeutics. Hemostasis is the natural physiological response of blood damage to the vasculature, ultimately leading to cessation of blood loss. Thrombosis that occurs in both arteries and veins is the virtual or total occlusion of a blood vessel by the elements of the hemostatic system. As the pathogenesis of arterial thrombosis clearly differs from that of venous thrombosis, the agents that inhibit platelet activity have the most benefit in the treatment of arterial thrombosis and, until recently, agents that inhibit the coagulation pathways have been used primarily for venous disease. From the widespread clinical study, aspirin has been generally accepted as a useful antithrombotic with a variety of arterial indications. Aspirin inhibits platelet aggregation by inhibiting generation of thromboxane A 2 (TXA 2 ) by activated platelets via acetylation of the enzyme cyclooxygenase. An alternative means of controlling TXA 2 -dependent aspects of platelet aggregation is by specific inhibition of thromboxane synthase. Ticlopidine is a thienopyridine derivative that has undergone extensive clinical testing and is a moderately active inhibitor of platelet aggregation. Factor Xa is an arginine directed endopeptidase responsible for the conversion of prothrombin to thrombin. Inhibition of this enzyme is a potential means to control aberrant coagulation and resulting thrombosis. The fibrinogen binding site on thrombin is also being explored as a potential site of action of therapeutic agents. Irreversible active-site inhibitors of thrombin, which target the serine in the catalytic site of thrombin, have also been developed. Based on the opportunities afforded by the advancement in molecular biology and by elucidation of the molecular basis of receptor/ligand and enzyme/substrate interactions, great strides have been made in the understanding of hemostasis and thrombosis.

Dibasic benzo[b]thiophene derivatives as A novel class of active site directed thrombin inhibitors : 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes

A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.

Fused bicyclic Gly-Asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

SOLID PHASE CHEMISTRY APPROACH TO THE SAR DEVELOPMENT OF A NOVEL CLASS OF ACTIVE SITE-DIRECTED THROMBIN INHIBITORS

Abstract A solid phase chemistry approach utilizing Mitsunobu chemistry, amine functionalization, and parallel purification was used to produce a diverse library of benzothiophene analogs. These analogs were used to advance the SAR of this class of molecules and give new directions for future studies.

Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.

Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.

Platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa) antagonists derived from amidinoindoles

Abstract A series of substituted amidinoindoles have been prepared as mimics of the RGD sequence and were studied as antagonists of the platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa). The agents were potent and selective antagonists of GPIIb–IIIa. Compared to their acyclic counterparts, the amidinoindole series bound with 10- to 20-fold greater affinity, indicating the advantages of added conformational restriction and/or hydrophobicity in the basic region of RGD mimics.

Characterization of LY806303 as a potent and selective inhibitor of thrombin

Abstract Methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carboxylate (LY806303; 1) has been characterized as a novel, potent and selective inhibitor thrombin.