Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant
[Display omitted] Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein,...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (3), p.444-450 |
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| creator | Raheem, Izzat T. Breslin, Michael J. Bruno, Joseph Cabalu, Tamara D. Cooke, Andrew Cox, Christopher D. Cui, Donghui Garson, Susan Gotter, Anthony L. Fox, Steven V. Harrell, C. Meacham Kuduk, Scott D. Lemaire, Wei Prueksaritanont, Thomayant Renger, John J. Stump, Craig Tannenbaum, Pamela L. Williams, Peter D. Winrow, Christopher J. Coleman, Paul J. |
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Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class. |
| doi_str_mv | 10.1016/j.bmcl.2014.12.056 |
| format | Article |
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Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.12.056</identifier><identifier>PMID: 25577040</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Active wake ; Animals ; Delta sleep ; Dogs ; Drug Evaluation, Preclinical ; Dual orexin receptor antagonist (DORA) ; Ethers - chemical synthesis ; Ethers - chemistry ; Ethers - pharmacokinetics ; Filorexant ; Half-Life ; Humans ; Orexin Receptor Antagonists ; Orexin Receptors - metabolism ; Piperidines - chemistry ; Piperidines - metabolism ; Protein Binding ; Pyrimidines - chemistry ; Pyrimidines - metabolism ; Rats ; REM sleep ; Selective orexin receptor antagonist (SORA) ; Sleep - drug effects ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (3), p.444-450</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-cdd68f75c7fe75cdde3f7c652d59b31d8a9b9998c650e4bca6fc966a043a63633</citedby><cites>FETCH-LOGICAL-c389t-cdd68f75c7fe75cdde3f7c652d59b31d8a9b9998c650e4bca6fc966a043a63633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X1401364X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25577040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Raheem, Izzat T.</creatorcontrib><creatorcontrib>Breslin, Michael J.</creatorcontrib><creatorcontrib>Bruno, Joseph</creatorcontrib><creatorcontrib>Cabalu, Tamara D.</creatorcontrib><creatorcontrib>Cooke, Andrew</creatorcontrib><creatorcontrib>Cox, Christopher D.</creatorcontrib><creatorcontrib>Cui, Donghui</creatorcontrib><creatorcontrib>Garson, Susan</creatorcontrib><creatorcontrib>Gotter, Anthony L.</creatorcontrib><creatorcontrib>Fox, Steven V.</creatorcontrib><creatorcontrib>Harrell, C. Meacham</creatorcontrib><creatorcontrib>Kuduk, Scott D.</creatorcontrib><creatorcontrib>Lemaire, Wei</creatorcontrib><creatorcontrib>Prueksaritanont, Thomayant</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><creatorcontrib>Stump, Craig</creatorcontrib><creatorcontrib>Tannenbaum, Pamela L.</creatorcontrib><creatorcontrib>Williams, Peter D.</creatorcontrib><creatorcontrib>Winrow, Christopher J.</creatorcontrib><creatorcontrib>Coleman, Paul J.</creatorcontrib><title>Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.</description><subject>Active wake</subject><subject>Animals</subject><subject>Delta sleep</subject><subject>Dogs</subject><subject>Drug Evaluation, Preclinical</subject><subject>Dual orexin receptor antagonist (DORA)</subject><subject>Ethers - chemical synthesis</subject><subject>Ethers - chemistry</subject><subject>Ethers - pharmacokinetics</subject><subject>Filorexant</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Orexin Receptor Antagonists</subject><subject>Orexin Receptors - metabolism</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - metabolism</subject><subject>Protein Binding</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - metabolism</subject><subject>Rats</subject><subject>REM sleep</subject><subject>Selective orexin receptor antagonist (SORA)</subject><subject>Sleep - drug effects</subject><subject>Structure-Activity Relationship</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>eNqNkUFrGzEQhUVpaFynf6CHoKNz2I200mpX0Etw0rRgCLQJ5Ca00iiRWa-20trU_z4yTnIsvczA8L0H8x5CXykpKaHicl12G9OXFaG8pFVJavEBzSgXvGCc1B_RjEhBilbyx1P0OaU1ySDh_BM6req6aQgnM-SufTJhB3GPg8OjHyF66wfAMD1DTFgnnKAHM_kd4BDhrx9wBAPjFCLWw6SfwuDTlPDi992vq3SB_ZBGH8Hibo-d7w-SjJ2hE6f7BF9e9xw9fL-5X_4oVne3P5dXq8KwVk6FsVa0rqlN4yBPa4G5xoi6srXsGLWtlp2Uss0nArwzWjgjhdCEMy2YYGyOFkffMYY_W0iT2uT_oO_1AGGbFBWCMEl41f4HWlec8kbIjFZH1MSQUgSnxug3Ou4VJepQhVqrQxXqUIWilcpVZNH5q_-224B9l7xln4FvRwByIDsPUSXjYTBgc35mUjb4f_m_AMlzm6k</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Raheem, Izzat T.</creator><creator>Breslin, Michael J.</creator><creator>Bruno, Joseph</creator><creator>Cabalu, Tamara D.</creator><creator>Cooke, Andrew</creator><creator>Cox, Christopher D.</creator><creator>Cui, Donghui</creator><creator>Garson, Susan</creator><creator>Gotter, Anthony L.</creator><creator>Fox, Steven V.</creator><creator>Harrell, C. 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Meacham</creatorcontrib><creatorcontrib>Kuduk, Scott D.</creatorcontrib><creatorcontrib>Lemaire, Wei</creatorcontrib><creatorcontrib>Prueksaritanont, Thomayant</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><creatorcontrib>Stump, Craig</creatorcontrib><creatorcontrib>Tannenbaum, Pamela L.</creatorcontrib><creatorcontrib>Williams, Peter D.</creatorcontrib><creatorcontrib>Winrow, Christopher J.</creatorcontrib><creatorcontrib>Coleman, Paul J.</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 - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Raheem, Izzat T.</au><au>Breslin, Michael J.</au><au>Bruno, Joseph</au><au>Cabalu, Tamara D.</au><au>Cooke, Andrew</au><au>Cox, Christopher D.</au><au>Cui, Donghui</au><au>Garson, Susan</au><au>Gotter, Anthony L.</au><au>Fox, Steven V.</au><au>Harrell, C. Meacham</au><au>Kuduk, Scott D.</au><au>Lemaire, Wei</au><au>Prueksaritanont, Thomayant</au><au>Renger, John J.</au><au>Stump, Craig</au><au>Tannenbaum, Pamela L.</au><au>Williams, Peter D.</au><au>Winrow, Christopher J.</au><au>Coleman, Paul J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>25</volume><issue>3</issue><spage>444</spage><epage>450</epage><pages>444-450</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25577040</pmid><doi>10.1016/j.bmcl.2014.12.056</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (3), p.444-450 |
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| subjects | Active wake Animals Delta sleep Dogs Drug Evaluation, Preclinical Dual orexin receptor antagonist (DORA) Ethers - chemical synthesis Ethers - chemistry Ethers - pharmacokinetics Filorexant Half-Life Humans Orexin Receptor Antagonists Orexin Receptors - metabolism Piperidines - chemistry Piperidines - metabolism Protein Binding Pyrimidines - chemistry Pyrimidines - metabolism Rats REM sleep Selective orexin receptor antagonist (SORA) Sleep - drug effects Structure-Activity Relationship |
| title | Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant |
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