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Development of AC265347‐Inspired Calcium‐Sensing Receptor Ago‐Positive Allosteric Modulators
The calcium‐sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR‐targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances,...
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| Published in: | ChemMedChem 2021-11, Vol.16 (22), p.3451-3462 |
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| cites | cdi_FETCH-LOGICAL-c3738-80cbaf0b3acae31fd4dbcf7432f81fefcebe81b85b40d063cffd998b3bd79a893 |
| container_end_page | 3462 |
| container_issue | 22 |
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| creator | Dinh, Le Vi DeBono, Aaron Keller, Andrew N. Josephs, Tracy M. Gregory, Karen J. Leach, Katie Capuano, Ben |
| description | The calcium‐sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR‐targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago‐PAM), AC265347, is chemically distinct from clinically‐approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347‐like compounds with diverse pharmacology and improved physicochemical and drug‐like properties.
Positive cooperativity: The CaSR is a clinical target in the treatment of hyperparathyroidism and related diseases. AC265347 is an ago‐PAM chemically distinct from clinically approved CaSR PAMs. AC265347 potently suppressed PTH release in rats and is virtually devoid of hypocalcaemia and may therefore offer unique clinical benefits. Herein we report an SAR study disclosing AC265347‐like compounds with diverse pharmacology and improved physicochemical characteristics. |
| doi_str_mv | 10.1002/cmdc.202100368 |
| format | article |
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Positive cooperativity: The CaSR is a clinical target in the treatment of hyperparathyroidism and related diseases. AC265347 is an ago‐PAM chemically distinct from clinically approved CaSR PAMs. AC265347 potently suppressed PTH release in rats and is virtually devoid of hypocalcaemia and may therefore offer unique clinical benefits. Herein we report an SAR study disclosing AC265347‐like compounds with diverse pharmacology and improved physicochemical characteristics.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.202100368</identifier><identifier>PMID: 34216111</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>AC265347 ; Allosteric properties ; Allosteric Regulation - drug effects ; Animals ; Calcium ; calcium-sensing receptor ; Calcium-sensing receptors ; class C GPCR ; Drug delivery ; Humans ; Hyperparathyroidism ; Hypocalcemia ; Models, Molecular ; Modulators ; Molecular Structure ; Nausea ; Parathyroid ; Parathyroid hormone ; Pharmacology ; positive allosteric modulators ; Rats ; Receptors ; Receptors, Calcium-Sensing - agonists ; Side effects ; Structure-Activity Relationship ; Vomiting</subject><ispartof>ChemMedChem, 2021-11, Vol.16 (22), p.3451-3462</ispartof><rights>2021 Wiley‐VCH GmbH</rights><rights>2021 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3738-80cbaf0b3acae31fd4dbcf7432f81fefcebe81b85b40d063cffd998b3bd79a893</citedby><cites>FETCH-LOGICAL-c3738-80cbaf0b3acae31fd4dbcf7432f81fefcebe81b85b40d063cffd998b3bd79a893</cites><orcidid>0000-0001-5434-0180 ; 0000-0002-9280-1803</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34216111$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dinh, Le Vi</creatorcontrib><creatorcontrib>DeBono, Aaron</creatorcontrib><creatorcontrib>Keller, Andrew N.</creatorcontrib><creatorcontrib>Josephs, Tracy M.</creatorcontrib><creatorcontrib>Gregory, Karen J.</creatorcontrib><creatorcontrib>Leach, Katie</creatorcontrib><creatorcontrib>Capuano, Ben</creatorcontrib><title>Development of AC265347‐Inspired Calcium‐Sensing Receptor Ago‐Positive Allosteric Modulators</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>The calcium‐sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR‐targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago‐PAM), AC265347, is chemically distinct from clinically‐approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347‐like compounds with diverse pharmacology and improved physicochemical and drug‐like properties.
Positive cooperativity: The CaSR is a clinical target in the treatment of hyperparathyroidism and related diseases. AC265347 is an ago‐PAM chemically distinct from clinically approved CaSR PAMs. AC265347 potently suppressed PTH release in rats and is virtually devoid of hypocalcaemia and may therefore offer unique clinical benefits. Herein we report an SAR study disclosing AC265347‐like compounds with diverse pharmacology and improved physicochemical characteristics.</description><subject>AC265347</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation - drug effects</subject><subject>Animals</subject><subject>Calcium</subject><subject>calcium-sensing receptor</subject><subject>Calcium-sensing receptors</subject><subject>class C GPCR</subject><subject>Drug delivery</subject><subject>Humans</subject><subject>Hyperparathyroidism</subject><subject>Hypocalcemia</subject><subject>Models, Molecular</subject><subject>Modulators</subject><subject>Molecular Structure</subject><subject>Nausea</subject><subject>Parathyroid</subject><subject>Parathyroid hormone</subject><subject>Pharmacology</subject><subject>positive allosteric modulators</subject><subject>Rats</subject><subject>Receptors</subject><subject>Receptors, Calcium-Sensing - agonists</subject><subject>Side effects</subject><subject>Structure-Activity Relationship</subject><subject>Vomiting</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNqFkMtu2zAQRYmiQe243XZZCMgmG7ukSEvU0lCeQIwUfawFPoYGDUpUSSlBdvmEfGO-JAzsuEA2Xc3MxZk7g4vQV4IXBOP8u2q1WuQ4TwMt-Ac0JbzA85Lw8uOhL6sJOo5xizFjnPBPaEJZTgpCyBTJM7gD5_sWuiHzJlvVebGkrHx-fLruYm8D6KwWTtmxTdIv6KLtNtlPUNAPPmSrjU_yDx_tYO8gWznn4wDBqmzt9ehEYuJndGSEi_BlX2foz8X57_pqfnN7eV2vbuaKlpTPOVZSGCypUAIoMZppqUzJaG44MWAUSOBE8qVkWOOCKmN0VXFJpS4rwSs6Q6c73z74vyPEoWltVOCc6MCPscmXjDNSFjlN6Mk7dOvH0KXvElXxijCeLszQYkep4GMMYJo-2FaEh4bg5jX95jX95pB-Wvi2tx1lC_qAv8WdgGoH3FsHD_-xa-r1Wf3P_AX9mpR2</recordid><startdate>20211119</startdate><enddate>20211119</enddate><creator>Dinh, Le Vi</creator><creator>DeBono, Aaron</creator><creator>Keller, Andrew N.</creator><creator>Josephs, Tracy M.</creator><creator>Gregory, Karen J.</creator><creator>Leach, Katie</creator><creator>Capuano, Ben</creator><general>Wiley Subscription Services, Inc</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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5434-0180</orcidid><orcidid>https://orcid.org/0000-0002-9280-1803</orcidid></search><sort><creationdate>20211119</creationdate><title>Development of AC265347‐Inspired Calcium‐Sensing Receptor Ago‐Positive Allosteric Modulators</title><author>Dinh, Le Vi ; DeBono, Aaron ; Keller, Andrew N. ; Josephs, Tracy M. ; Gregory, Karen J. ; Leach, Katie ; Capuano, Ben</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3738-80cbaf0b3acae31fd4dbcf7432f81fefcebe81b85b40d063cffd998b3bd79a893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AC265347</topic><topic>Allosteric properties</topic><topic>Allosteric Regulation - drug effects</topic><topic>Animals</topic><topic>Calcium</topic><topic>calcium-sensing receptor</topic><topic>Calcium-sensing receptors</topic><topic>class C GPCR</topic><topic>Drug delivery</topic><topic>Humans</topic><topic>Hyperparathyroidism</topic><topic>Hypocalcemia</topic><topic>Models, Molecular</topic><topic>Modulators</topic><topic>Molecular Structure</topic><topic>Nausea</topic><topic>Parathyroid</topic><topic>Parathyroid hormone</topic><topic>Pharmacology</topic><topic>positive allosteric modulators</topic><topic>Rats</topic><topic>Receptors</topic><topic>Receptors, Calcium-Sensing - agonists</topic><topic>Side effects</topic><topic>Structure-Activity Relationship</topic><topic>Vomiting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dinh, Le Vi</creatorcontrib><creatorcontrib>DeBono, Aaron</creatorcontrib><creatorcontrib>Keller, Andrew N.</creatorcontrib><creatorcontrib>Josephs, Tracy M.</creatorcontrib><creatorcontrib>Gregory, Karen J.</creatorcontrib><creatorcontrib>Leach, Katie</creatorcontrib><creatorcontrib>Capuano, Ben</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dinh, Le Vi</au><au>DeBono, Aaron</au><au>Keller, Andrew N.</au><au>Josephs, Tracy M.</au><au>Gregory, Karen J.</au><au>Leach, Katie</au><au>Capuano, Ben</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of AC265347‐Inspired Calcium‐Sensing Receptor Ago‐Positive Allosteric Modulators</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2021-11-19</date><risdate>2021</risdate><volume>16</volume><issue>22</issue><spage>3451</spage><epage>3462</epage><pages>3451-3462</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>The calcium‐sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR‐targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago‐PAM), AC265347, is chemically distinct from clinically‐approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347‐like compounds with diverse pharmacology and improved physicochemical and drug‐like properties.
Positive cooperativity: The CaSR is a clinical target in the treatment of hyperparathyroidism and related diseases. AC265347 is an ago‐PAM chemically distinct from clinically approved CaSR PAMs. AC265347 potently suppressed PTH release in rats and is virtually devoid of hypocalcaemia and may therefore offer unique clinical benefits. Herein we report an SAR study disclosing AC265347‐like compounds with diverse pharmacology and improved physicochemical characteristics.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34216111</pmid><doi>10.1002/cmdc.202100368</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5434-0180</orcidid><orcidid>https://orcid.org/0000-0002-9280-1803</orcidid></addata></record> |
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| subjects | AC265347 Allosteric properties Allosteric Regulation - drug effects Animals Calcium calcium-sensing receptor Calcium-sensing receptors class C GPCR Drug delivery Humans Hyperparathyroidism Hypocalcemia Models, Molecular Modulators Molecular Structure Nausea Parathyroid Parathyroid hormone Pharmacology positive allosteric modulators Rats Receptors Receptors, Calcium-Sensing - agonists Side effects Structure-Activity Relationship Vomiting |
| title | Development of AC265347‐Inspired Calcium‐Sensing Receptor Ago‐Positive Allosteric Modulators |
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