Ocular Hypotensive Response in Nonhuman Primates of (8R)‑1-[(2S)‑2-Aminopropyl]-8,9-dihydro‑7H‑pyrano[2,3‑g]indazol-8-ol a Selective 5‑HT2 Receptor Agonist
Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-11, Vol.58 (22), p.8818-8833 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 58 |
| creator | May, Jesse A Sharif, Najam A McLaughlin, Marsha A Chen, Hwang-Hsing Severns, Bryon S Kelly, Curtis R Holt, William F Young, Richard Glennon, Richard A Hellberg, Mark R Dean, Thomas R |
| description | Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans. |
| doi_str_mv | 10.1021/acs.jmedchem.5b00857 |
| format | Article |
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Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b00857</identifier><identifier>PMID: 26551970</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Topical ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Benzophenones - administration & dosage ; Benzophenones - therapeutic use ; Bromobenzenes - administration & dosage ; Bromobenzenes - therapeutic use ; Cornea - metabolism ; Glaucoma - drug therapy ; HT29 Cells ; Humans ; In Vitro Techniques ; Indazoles - adverse effects ; Indazoles - chemical synthesis ; Indazoles - therapeutic use ; Indicators and Reagents ; Intraocular Pressure - drug effects ; Macaca fascicularis ; Ocular Hypertension - drug therapy ; Permeability ; Rats ; Receptors, Adrenergic, alpha - metabolism ; Receptors, Serotonin - metabolism ; Serotonin 5-HT2 Receptor Agonists - adverse effects ; Serotonin 5-HT2 Receptor Agonists - therapeutic use ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2015-11, Vol.58 (22), p.8818-8833</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b00857$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00857$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26551970$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>May, Jesse A</creatorcontrib><creatorcontrib>Sharif, Najam A</creatorcontrib><creatorcontrib>McLaughlin, Marsha A</creatorcontrib><creatorcontrib>Chen, Hwang-Hsing</creatorcontrib><creatorcontrib>Severns, Bryon S</creatorcontrib><creatorcontrib>Kelly, Curtis R</creatorcontrib><creatorcontrib>Holt, William F</creatorcontrib><creatorcontrib>Young, Richard</creatorcontrib><creatorcontrib>Glennon, Richard A</creatorcontrib><creatorcontrib>Hellberg, Mark R</creatorcontrib><creatorcontrib>Dean, Thomas R</creatorcontrib><title>Ocular Hypotensive Response in Nonhuman Primates of (8R)‑1-[(2S)‑2-Aminopropyl]-8,9-dihydro‑7H‑pyrano[2,3‑g]indazol-8-ol a Selective 5‑HT2 Receptor Agonist</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.</description><subject>Administration, Topical</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - administration & dosage</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>Benzophenones - administration & dosage</subject><subject>Benzophenones - therapeutic use</subject><subject>Bromobenzenes - administration & dosage</subject><subject>Bromobenzenes - therapeutic use</subject><subject>Cornea - metabolism</subject><subject>Glaucoma - drug therapy</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Indazoles - adverse effects</subject><subject>Indazoles - chemical synthesis</subject><subject>Indazoles - therapeutic use</subject><subject>Indicators and Reagents</subject><subject>Intraocular Pressure - drug effects</subject><subject>Macaca fascicularis</subject><subject>Ocular Hypertension - drug therapy</subject><subject>Permeability</subject><subject>Rats</subject><subject>Receptors, Adrenergic, alpha - metabolism</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin 5-HT2 Receptor Agonists - adverse effects</subject><subject>Serotonin 5-HT2 Receptor Agonists - therapeutic use</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kcFu1DAQQC0EokvhDxDycZHqZTyTrO3jqqIsUkVRW05VFXkTbzerxA5xgpSe-AW-gv_iS_DS5TIee57s8TzG3kpYSED5wZZxsW9dVe5cu8g3ADpXz9hM5ggi05A9ZzMARIFLpBP2KsY9AJBEeslOcJnn0iiYsd9X5djYnq-nLgzOx_qH49cudsFHx2vPvwS_G1vr-de-bu3gIg9bPtfX7__8_CXF3RxvDhmKVVv70PWhm5p7oc-MqOrdVPUhFdU6hW7qrQ93eEZp83Bf-8o-hkZoERpu-Y1rXDkc3s5TeX2LqYfSdUPo-eoh-DoOr9mLrW2ie3NcT9m3i4-352txefXp8_nqUljMcRCEOgNLZKRGcnJLThlT5aCpImNUllFWZtYAadRASmGFmxISpDcOzZbolM2f7k1_-T66OBRtHUvXNNa7MMZCKloulQGtEvruiI6b5KHoDhPqp-L_cBMAT0BSVezD2PvUeSGhOPgr_h0e_RVHf_QXT0KSMw</recordid><startdate>20151125</startdate><enddate>20151125</enddate><creator>May, Jesse A</creator><creator>Sharif, Najam A</creator><creator>McLaughlin, Marsha A</creator><creator>Chen, Hwang-Hsing</creator><creator>Severns, Bryon S</creator><creator>Kelly, Curtis R</creator><creator>Holt, William F</creator><creator>Young, Richard</creator><creator>Glennon, Richard A</creator><creator>Hellberg, Mark R</creator><creator>Dean, Thomas R</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20151125</creationdate><title>Ocular Hypotensive Response in Nonhuman Primates of (8R)‑1-[(2S)‑2-Aminopropyl]-8,9-dihydro‑7H‑pyrano[2,3‑g]indazol-8-ol a Selective 5‑HT2 Receptor Agonist</title><author>May, Jesse A ; Sharif, Najam A ; McLaughlin, Marsha A ; Chen, Hwang-Hsing ; Severns, Bryon S ; Kelly, Curtis R ; Holt, William F ; Young, Richard ; Glennon, Richard A ; Hellberg, Mark R ; Dean, Thomas R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a252t-32840a3391823e1f3e799d5083d39974434c4a90382803772d2bc0e798be29f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Topical</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - administration & dosage</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>Benzophenones - administration & dosage</topic><topic>Benzophenones - therapeutic use</topic><topic>Bromobenzenes - administration & dosage</topic><topic>Bromobenzenes - therapeutic use</topic><topic>Cornea - metabolism</topic><topic>Glaucoma - drug therapy</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Indazoles - adverse effects</topic><topic>Indazoles - chemical synthesis</topic><topic>Indazoles - therapeutic use</topic><topic>Indicators and Reagents</topic><topic>Intraocular Pressure - drug effects</topic><topic>Macaca fascicularis</topic><topic>Ocular Hypertension - drug therapy</topic><topic>Permeability</topic><topic>Rats</topic><topic>Receptors, Adrenergic, alpha - metabolism</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin 5-HT2 Receptor Agonists - adverse effects</topic><topic>Serotonin 5-HT2 Receptor Agonists - therapeutic use</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>May, Jesse A</creatorcontrib><creatorcontrib>Sharif, Najam A</creatorcontrib><creatorcontrib>McLaughlin, Marsha A</creatorcontrib><creatorcontrib>Chen, Hwang-Hsing</creatorcontrib><creatorcontrib>Severns, Bryon S</creatorcontrib><creatorcontrib>Kelly, Curtis R</creatorcontrib><creatorcontrib>Holt, William F</creatorcontrib><creatorcontrib>Young, Richard</creatorcontrib><creatorcontrib>Glennon, Richard A</creatorcontrib><creatorcontrib>Hellberg, Mark R</creatorcontrib><creatorcontrib>Dean, Thomas R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>May, Jesse A</au><au>Sharif, Najam A</au><au>McLaughlin, Marsha A</au><au>Chen, Hwang-Hsing</au><au>Severns, Bryon S</au><au>Kelly, Curtis R</au><au>Holt, William F</au><au>Young, Richard</au><au>Glennon, Richard A</au><au>Hellberg, Mark R</au><au>Dean, Thomas R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ocular Hypotensive Response in Nonhuman Primates of (8R)‑1-[(2S)‑2-Aminopropyl]-8,9-dihydro‑7H‑pyrano[2,3‑g]indazol-8-ol a Selective 5‑HT2 Receptor Agonist</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2015-11, Vol.58 (22), p.8818-8833 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Administration, Topical Animals Anti-Inflammatory Agents, Non-Steroidal - administration & dosage Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Benzophenones - administration & dosage Benzophenones - therapeutic use Bromobenzenes - administration & dosage Bromobenzenes - therapeutic use Cornea - metabolism Glaucoma - drug therapy HT29 Cells Humans In Vitro Techniques Indazoles - adverse effects Indazoles - chemical synthesis Indazoles - therapeutic use Indicators and Reagents Intraocular Pressure - drug effects Macaca fascicularis Ocular Hypertension - drug therapy Permeability Rats Receptors, Adrenergic, alpha - metabolism Receptors, Serotonin - metabolism Serotonin 5-HT2 Receptor Agonists - adverse effects Serotonin 5-HT2 Receptor Agonists - therapeutic use Structure-Activity Relationship |
| title | Ocular Hypotensive Response in Nonhuman Primates of (8R)‑1-[(2S)‑2-Aminopropyl]-8,9-dihydro‑7H‑pyrano[2,3‑g]indazol-8-ol a Selective 5‑HT2 Receptor Agonist |
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