Karen Lynn Lobb

The non-pfjptide NK-1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.

Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

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

Diphenylpyrazolidinone and benzodiazepine cholecystokinin antagonists: A case of convergent evolution in medicinal chemistry

Abstract Two recently described classes of nonpeptide cholecystokinin receptor antagonists contain diphenylpyrazolidinone and benzodiazepine substructures, respectively. Although the origins and development of these series were completely independent, the low energy conformations predicted by modeling showed remarkable three-dimensional homology between the structures.

Expedited discovery of second generation NK-1 antagonists: identification of a nonbasic aryloxy substituent

Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.