Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT 4 Receptor Partial Agonists
Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT receptor (5-HT R) offer both...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-06, Vol.61 (11), p.4993-5008 |
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| creator | Nirogi, Ramakrishna Mohammed, Abdul Rasheed Shinde, Anil K Gagginapally, Shankar Reddy Kancharla, Durga Malleshwari Middekadi, Vanaja Reddy Bogaraju, Narsimha Ravella, Srinivasa Rao Singh, Pooja Birangal, Sumit Raosaheb Subramanian, Ramkumar Palacharla, Raghava Choudary Benade, Vijay Muddana, Nageswararao Jayarajan, Pradeep |
| description | Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT
receptor (5-HT
R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT
R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT
R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT
R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model. |
| doi_str_mv | 10.1021/acs.jmedchem.8b00457 |
| format | Article |
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receptor (5-HT
R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT
R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT
R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT
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receptor (5-HT
R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT
R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT
R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT
R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.</description><subject>Amides - chemistry</subject><subject>Animals</subject><subject>Chemistry Techniques, Synthetic</subject><subject>Drug Evaluation, Preclinical</subject><subject>Humans</subject><subject>Male</subject><subject>Oxadiazoles - chemical synthesis</subject><subject>Oxadiazoles - chemistry</subject><subject>Oxadiazoles - pharmacokinetics</subject><subject>Oxadiazoles - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Serotonin, 5-HT4 - metabolism</subject><subject>Serotonin 5-HT4 Receptor Agonists - chemistry</subject><subject>Serotonin 5-HT4 Receptor Agonists - pharmacokinetics</subject><subject>Serotonin 5-HT4 Receptor Agonists - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kNtOAjEQhhujEUTfwJg-AIs97emSIIoJCUTwetPtzkrJHkhbiPg-vqfl5NUkM9__T_Ih9EjJgBJGn6Wyg3UNhVpBPUhyQkQYX6EuDRkJRELENeoSwljAIsY76M7aNSGEU8ZvUYelccQ5EV30u9g3bgVW2z5eOLNVbmsgGCqnd9rt8QdU0um2sSu98YRsCjw3oCrdaCUrPN7JansEcFviCTgwrTRt7VcKD2tdgD1maJ_3RTD7loWWP20F-AWM3nlqdwAsDoPJEgv_TcHGtQbPpXHa9w-_2kZbZ-_RTSkrCw_n2UOfr-PlaBJMZ2_vo-E0UDRJXZAyJQiVoYpUnCgJkSwjKCVNwgRELkKV5DyM41hQCjFLSo_TNC5ExKksISW8h8SpV5nWWgNltjG6lmafUZIdrGfeenaxnp2t-9jTKbbZ5v72H7po5n_UIIPO</recordid><startdate>20180614</startdate><enddate>20180614</enddate><creator>Nirogi, Ramakrishna</creator><creator>Mohammed, Abdul Rasheed</creator><creator>Shinde, Anil K</creator><creator>Gagginapally, Shankar Reddy</creator><creator>Kancharla, Durga Malleshwari</creator><creator>Middekadi, Vanaja Reddy</creator><creator>Bogaraju, Narsimha</creator><creator>Ravella, Srinivasa Rao</creator><creator>Singh, Pooja</creator><creator>Birangal, Sumit Raosaheb</creator><creator>Subramanian, Ramkumar</creator><creator>Palacharla, Raghava Choudary</creator><creator>Benade, Vijay</creator><creator>Muddana, Nageswararao</creator><creator>Jayarajan, Pradeep</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-2045-0784</orcidid></search><sort><creationdate>20180614</creationdate><title>Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT 4 Receptor Partial Agonists</title><author>Nirogi, Ramakrishna ; Mohammed, Abdul Rasheed ; Shinde, Anil K ; Gagginapally, Shankar Reddy ; Kancharla, Durga Malleshwari ; Middekadi, Vanaja Reddy ; Bogaraju, Narsimha ; Ravella, Srinivasa Rao ; Singh, Pooja ; Birangal, Sumit Raosaheb ; Subramanian, Ramkumar ; Palacharla, Raghava Choudary ; Benade, Vijay ; Muddana, Nageswararao ; Jayarajan, Pradeep</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c189t-92c401a5c6c78cae6af6efa1858e4b45c8b35777411e728f2c4197d4631afe903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Amides - chemistry</topic><topic>Animals</topic><topic>Chemistry Techniques, Synthetic</topic><topic>Drug Evaluation, Preclinical</topic><topic>Humans</topic><topic>Male</topic><topic>Oxadiazoles - chemical synthesis</topic><topic>Oxadiazoles - chemistry</topic><topic>Oxadiazoles - pharmacokinetics</topic><topic>Oxadiazoles - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Serotonin, 5-HT4 - metabolism</topic><topic>Serotonin 5-HT4 Receptor Agonists - chemistry</topic><topic>Serotonin 5-HT4 Receptor Agonists - pharmacokinetics</topic><topic>Serotonin 5-HT4 Receptor Agonists - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nirogi, Ramakrishna</creatorcontrib><creatorcontrib>Mohammed, Abdul Rasheed</creatorcontrib><creatorcontrib>Shinde, Anil K</creatorcontrib><creatorcontrib>Gagginapally, Shankar Reddy</creatorcontrib><creatorcontrib>Kancharla, Durga Malleshwari</creatorcontrib><creatorcontrib>Middekadi, Vanaja Reddy</creatorcontrib><creatorcontrib>Bogaraju, Narsimha</creatorcontrib><creatorcontrib>Ravella, Srinivasa Rao</creatorcontrib><creatorcontrib>Singh, Pooja</creatorcontrib><creatorcontrib>Birangal, Sumit Raosaheb</creatorcontrib><creatorcontrib>Subramanian, Ramkumar</creatorcontrib><creatorcontrib>Palacharla, Raghava Choudary</creatorcontrib><creatorcontrib>Benade, Vijay</creatorcontrib><creatorcontrib>Muddana, Nageswararao</creatorcontrib><creatorcontrib>Jayarajan, Pradeep</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nirogi, Ramakrishna</au><au>Mohammed, Abdul Rasheed</au><au>Shinde, Anil K</au><au>Gagginapally, Shankar Reddy</au><au>Kancharla, Durga Malleshwari</au><au>Middekadi, Vanaja Reddy</au><au>Bogaraju, Narsimha</au><au>Ravella, Srinivasa Rao</au><au>Singh, Pooja</au><au>Birangal, Sumit Raosaheb</au><au>Subramanian, Ramkumar</au><au>Palacharla, Raghava Choudary</au><au>Benade, Vijay</au><au>Muddana, Nageswararao</au><au>Jayarajan, Pradeep</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT 4 Receptor Partial Agonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2018-06-14</date><risdate>2018</risdate><volume>61</volume><issue>11</issue><spage>4993</spage><epage>5008</epage><pages>4993-5008</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT
receptor (5-HT
R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT
R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT
R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT
R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.</abstract><cop>United States</cop><pmid>29763304</pmid><doi>10.1021/acs.jmedchem.8b00457</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-2045-0784</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2018-06, Vol.61 (11), p.4993-5008 |
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| source | ACS Publications; MEDLINE |
| subjects | Amides - chemistry Animals Chemistry Techniques, Synthetic Drug Evaluation, Preclinical Humans Male Oxadiazoles - chemical synthesis Oxadiazoles - chemistry Oxadiazoles - pharmacokinetics Oxadiazoles - pharmacology Rats Rats, Wistar Receptors, Serotonin, 5-HT4 - metabolism Serotonin 5-HT4 Receptor Agonists - chemistry Serotonin 5-HT4 Receptor Agonists - pharmacokinetics Serotonin 5-HT4 Receptor Agonists - pharmacology Structure-Activity Relationship |
| title | Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT 4 Receptor Partial Agonists |
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