Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

Tremblay, Martin; Lescarbeau, André; Grogan, Michael J.; E, Tan; Lin, Grace; Austad, Brian C.; Yu, Lin-Chen; Behnke, Mark L.; Nair, Somarajan; Hagel, Margit; White, Kerry; Conley, James; Manna, Joseph; Alvarez-Diez, Teresa M.; Hoyt, Jennifer; Woodward, Caroline; Sydor, Jens; Pink, Melissa; MacDougall, John R.; Campbell, Matthew; Cushing, Jill; Ferguson, J; Curtis, Michael S.; McGovern, Karen; Read, Margaret; Palombella, Vito J.; Adams, Julian; Castro, Alfredo

doi:10.1021/jm900305z

Cited by 230 publications

(168 citation statements)

References 56 publications

(122 reference statements)

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“…47 In their 5-HT 1 receptor ligand program, the metabolism of the analogue containing the 1,4-diazepane (58) was greatly improved by replacing the ring with piperidine rings (59,61) or a piperazine ring (60). While the N-methylpiperazine derivative (60) and N-methylpiperidine derivative (61) had similar stability in RLM, 61 had lower in vivo rat clearance. In this set of compounds there is no correlation of cLogD 7.4 with metabolic stability, suggesting the ring size had more of an influence on metabolism.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

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Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

“…In vivo PK experiments were conducted with SD rats (iv dose of 1 mg/kg, po dose of 5 mg/kg). 60 Figure 28. In vitro potency and LM data for selected GlyT1 receptor antagonists 63 (%TO = percent turnover).…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…9,14,18,19 Given that 5m displayed both a favorable PK profile across preclinical species and brain exposure upon oral administration, we elected to assess its antitumor efficacy using both subcutaneous and orthotopic Ptch þ/-p53 -/-medulloblastoma allograft models.…”

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confidence: 99%

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

Pan

Jiang

et al. 2010

ACS Med. Chem. Lett.

294

236

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The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic highthroughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4 0 -(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.

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“…51 The latter is activated in many kinds of tumor cells, and recent evidence suggests that blocking aberrant Hh pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancers. [52][53][54] These data suggest that the induction of KIF7 expression or activity may control human cancers effectively and, thus, may be used as a therapeutic tool.…”

Section: Kinesin-4 Familymentioning

confidence: 99%

The role of kinesin family proteins in tumorigenesis and progression

Feng

2010

Cancer

112

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The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010;116:5150-60.

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Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

Cited by 230 publications

References 56 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

The role of kinesin family proteins in tumorigenesis and progression

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