Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility
[Display omitted] Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the im...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (3), p.529-541 |
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| creator | Zak, Mark Liederer, Bianca M. Sampath, Deepak Yuen, Po-wai Bair, Kenneth W. Baumeister, Timm Buckmelter, Alexandre J. Clodfelter, Karl H. Cheng, Eric Crocker, Lisa Fu, Bang Han, Bingsong Li, Guangkun Ho, Yen-Ching Lin, Jian Liu, Xiongcai Ly, Justin O’Brien, Thomas Reynolds, Dominic J. Skelton, Nicholas Smith, Chase C. Tay, Suzanne Wang, Weiru Wang, Zhongguo Xiao, Yang Zhang, Lei Zhao, Guiling Zheng, Xiaozhang Dragovich, Peter S. |
| description | [Display omitted]
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies. |
| doi_str_mv | 10.1016/j.bmcl.2014.12.026 |
| format | Article |
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Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.12.026</identifier><identifier>PMID: 25556090</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Aqueous solubility ; Binding Sites ; Cell Line, Tumor ; Cell Membrane Permeability - drug effects ; Cell Proliferation - drug effects ; Crystallography, X-Ray ; CYP TDI ; Cytochrome P-450 CYP3A - chemistry ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 CYP3A Inhibitors - chemistry ; Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics ; Cytochrome P-450 CYP3A Inhibitors - toxicity ; Cytochrome P450 time-dependent inhibition ; Dogs ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - therapeutic use ; Female ; Half-Life ; Humans ; Kinetics ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Nude ; Molecular Dynamics Simulation ; NAMPT ; Neoplasms - drug therapy ; Neoplasms - pathology ; Nicotinamide phosphoribosyltransferase ; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors ; Nicotinamide Phosphoribosyltransferase - metabolism ; Protein Binding ; Protein Structure, Tertiary ; Pyrimidines - chemistry ; Pyrimidines - therapeutic use ; Pyrimidines - toxicity ; Solubility ; Structure-Activity Relationship ; Thermodynamics ; Transplantation, Heterologous ; Tumor metabolism ; Water - chemistry</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (3), p.529-541</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-97bc488387322f3f304758d1692a2599c9a94bceb637fe7cd5fd1eb71085a0893</citedby><cites>FETCH-LOGICAL-c389t-97bc488387322f3f304758d1692a2599c9a94bceb637fe7cd5fd1eb71085a0893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X14013237$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25556090$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zak, Mark</creatorcontrib><creatorcontrib>Liederer, Bianca M.</creatorcontrib><creatorcontrib>Sampath, Deepak</creatorcontrib><creatorcontrib>Yuen, Po-wai</creatorcontrib><creatorcontrib>Bair, Kenneth W.</creatorcontrib><creatorcontrib>Baumeister, Timm</creatorcontrib><creatorcontrib>Buckmelter, Alexandre J.</creatorcontrib><creatorcontrib>Clodfelter, Karl H.</creatorcontrib><creatorcontrib>Cheng, Eric</creatorcontrib><creatorcontrib>Crocker, Lisa</creatorcontrib><creatorcontrib>Fu, Bang</creatorcontrib><creatorcontrib>Han, Bingsong</creatorcontrib><creatorcontrib>Li, Guangkun</creatorcontrib><creatorcontrib>Ho, Yen-Ching</creatorcontrib><creatorcontrib>Lin, Jian</creatorcontrib><creatorcontrib>Liu, Xiongcai</creatorcontrib><creatorcontrib>Ly, Justin</creatorcontrib><creatorcontrib>O’Brien, Thomas</creatorcontrib><creatorcontrib>Reynolds, Dominic J.</creatorcontrib><creatorcontrib>Skelton, Nicholas</creatorcontrib><creatorcontrib>Smith, Chase C.</creatorcontrib><creatorcontrib>Tay, Suzanne</creatorcontrib><creatorcontrib>Wang, Weiru</creatorcontrib><creatorcontrib>Wang, Zhongguo</creatorcontrib><creatorcontrib>Xiao, Yang</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Zhao, Guiling</creatorcontrib><creatorcontrib>Zheng, Xiaozhang</creatorcontrib><creatorcontrib>Dragovich, Peter S.</creatorcontrib><title>Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.</description><subject>Animals</subject><subject>Aqueous solubility</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Crystallography, X-Ray</subject><subject>CYP TDI</subject><subject>Cytochrome P-450 CYP3A - chemistry</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Cytochrome P-450 CYP3A Inhibitors - chemistry</subject><subject>Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics</subject><subject>Cytochrome P-450 CYP3A Inhibitors - toxicity</subject><subject>Cytochrome P450 time-dependent inhibition</subject><subject>Dogs</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Female</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Madin Darby Canine Kidney Cells</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular Dynamics Simulation</subject><subject>NAMPT</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Nicotinamide phosphoribosyltransferase</subject><subject>Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors</subject><subject>Nicotinamide Phosphoribosyltransferase - metabolism</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - therapeutic use</subject><subject>Pyrimidines - toxicity</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Thermodynamics</subject><subject>Transplantation, Heterologous</subject><subject>Tumor metabolism</subject><subject>Water - chemistry</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EokPhBVggL8siwb9JLLEZjQpUKtBFkWBlOfaNxqPEHmzPoHkbHpVE07JELK7u5jvnHt2D0GtKakpo825X95Mda0aoqCmrCWueoBUVjai4IPIpWhHVkKpT4vsFepHzjswgEeI5umBSyoYoskK_bxyE4gdvTfEx4Djg4G0sPpjJO8D7bczzJN_HfBpLMiEPkEwGfPVl_fnu_i32Yet7X2LK-JcvWxwihuMsDRYWt82PO74WuPgJKgd7CMu9R9Fy0QSH_bRP8QgOm58HiIeMcxwPvR99Ob1EzwYzZnj1sC_Rtw_X95tP1e3Xjzeb9W1leadKpdreiq7jXcsZG_jAiWhl52ijmGFSKauMEr2FvuHtAK11cnAU-paSThrSKX6Jrs6-c5I5RC568tnCOJqwJNK0aTnvOJXyP1DJBFVNu6DsjNoUc04w6H3yk0knTYleStQ7vZSolxI1ZXoucRa9efA_9BO4v5LH1mbg_RmA-SFHD0ln65eHO5_AFu2i_5f_HxgYsGg</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Zak, Mark</creator><creator>Liederer, Bianca M.</creator><creator>Sampath, Deepak</creator><creator>Yuen, Po-wai</creator><creator>Bair, Kenneth W.</creator><creator>Baumeister, Timm</creator><creator>Buckmelter, Alexandre J.</creator><creator>Clodfelter, Karl H.</creator><creator>Cheng, Eric</creator><creator>Crocker, Lisa</creator><creator>Fu, Bang</creator><creator>Han, Bingsong</creator><creator>Li, Guangkun</creator><creator>Ho, Yen-Ching</creator><creator>Lin, Jian</creator><creator>Liu, Xiongcai</creator><creator>Ly, Justin</creator><creator>O’Brien, Thomas</creator><creator>Reynolds, Dominic J.</creator><creator>Skelton, Nicholas</creator><creator>Smith, Chase C.</creator><creator>Tay, Suzanne</creator><creator>Wang, Weiru</creator><creator>Wang, Zhongguo</creator><creator>Xiao, Yang</creator><creator>Zhang, Lei</creator><creator>Zhao, Guiling</creator><creator>Zheng, Xiaozhang</creator><creator>Dragovich, Peter S.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20150201</creationdate><title>Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility</title><author>Zak, Mark ; Liederer, Bianca M. ; Sampath, Deepak ; Yuen, Po-wai ; Bair, Kenneth W. ; Baumeister, Timm ; Buckmelter, Alexandre J. ; Clodfelter, Karl H. ; Cheng, Eric ; Crocker, Lisa ; Fu, Bang ; Han, Bingsong ; Li, Guangkun ; Ho, Yen-Ching ; Lin, Jian ; Liu, Xiongcai ; Ly, Justin ; O’Brien, Thomas ; Reynolds, Dominic J. ; Skelton, Nicholas ; Smith, Chase C. ; Tay, Suzanne ; Wang, Weiru ; Wang, Zhongguo ; Xiao, Yang ; Zhang, Lei ; Zhao, Guiling ; Zheng, Xiaozhang ; Dragovich, Peter S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-97bc488387322f3f304758d1692a2599c9a94bceb637fe7cd5fd1eb71085a0893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Aqueous solubility</topic><topic>Binding Sites</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane Permeability - 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antagonists & inhibitors</topic><topic>Nicotinamide Phosphoribosyltransferase - metabolism</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - therapeutic use</topic><topic>Pyrimidines - toxicity</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Thermodynamics</topic><topic>Transplantation, Heterologous</topic><topic>Tumor metabolism</topic><topic>Water - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zak, Mark</creatorcontrib><creatorcontrib>Liederer, Bianca M.</creatorcontrib><creatorcontrib>Sampath, Deepak</creatorcontrib><creatorcontrib>Yuen, Po-wai</creatorcontrib><creatorcontrib>Bair, Kenneth W.</creatorcontrib><creatorcontrib>Baumeister, Timm</creatorcontrib><creatorcontrib>Buckmelter, Alexandre J.</creatorcontrib><creatorcontrib>Clodfelter, Karl H.</creatorcontrib><creatorcontrib>Cheng, Eric</creatorcontrib><creatorcontrib>Crocker, Lisa</creatorcontrib><creatorcontrib>Fu, Bang</creatorcontrib><creatorcontrib>Han, Bingsong</creatorcontrib><creatorcontrib>Li, Guangkun</creatorcontrib><creatorcontrib>Ho, Yen-Ching</creatorcontrib><creatorcontrib>Lin, Jian</creatorcontrib><creatorcontrib>Liu, Xiongcai</creatorcontrib><creatorcontrib>Ly, Justin</creatorcontrib><creatorcontrib>O’Brien, Thomas</creatorcontrib><creatorcontrib>Reynolds, Dominic J.</creatorcontrib><creatorcontrib>Skelton, Nicholas</creatorcontrib><creatorcontrib>Smith, Chase C.</creatorcontrib><creatorcontrib>Tay, Suzanne</creatorcontrib><creatorcontrib>Wang, Weiru</creatorcontrib><creatorcontrib>Wang, Zhongguo</creatorcontrib><creatorcontrib>Xiao, Yang</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Zhao, Guiling</creatorcontrib><creatorcontrib>Zheng, Xiaozhang</creatorcontrib><creatorcontrib>Dragovich, Peter S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - 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Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25556090</pmid><doi>10.1016/j.bmcl.2014.12.026</doi><tpages>13</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (3), p.529-541 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Aqueous solubility Binding Sites Cell Line, Tumor Cell Membrane Permeability - drug effects Cell Proliferation - drug effects Crystallography, X-Ray CYP TDI Cytochrome P-450 CYP3A - chemistry Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inhibitors - chemistry Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics Cytochrome P-450 CYP3A Inhibitors - toxicity Cytochrome P450 time-dependent inhibition Dogs Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - therapeutic use Female Half-Life Humans Kinetics Madin Darby Canine Kidney Cells Mice Mice, Nude Molecular Dynamics Simulation NAMPT Neoplasms - drug therapy Neoplasms - pathology Nicotinamide phosphoribosyltransferase Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors Nicotinamide Phosphoribosyltransferase - metabolism Protein Binding Protein Structure, Tertiary Pyrimidines - chemistry Pyrimidines - therapeutic use Pyrimidines - toxicity Solubility Structure-Activity Relationship Thermodynamics Transplantation, Heterologous Tumor metabolism Water - chemistry |
| title | Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility |
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