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Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates
A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-ph...
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Published in: | Journal of medicinal chemistry 1998-05, Vol.41 (11), p.1827-1837 |
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creator | Iqbal, Nadeem Akula, Murthy R Vo, Dean Matowe, Wandikayi C McEwen, Carol-Anne Wolowyk, Michael W Knaus, Edward E |
description | A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels. |
doi_str_mv | 10.1021/jm970529f |
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Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970529f</identifier><identifier>PMID: 9599233</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Atrial Function ; Biological and medical sciences ; Calcium Channel Agonists - chemical synthesis ; Calcium Channel Agonists - chemistry ; Calcium Channel Agonists - pharmacology ; Calcium Channel Blockers - chemical synthesis ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - pharmacology ; Calcium Channels - drug effects ; Cardiovascular system ; congestive heart failure ; Guinea Pigs ; Heart Atria - drug effects ; Hydrogen Bonding ; Ileum - drug effects ; Ileum - physiology ; In Vitro Techniques ; Medical sciences ; Miscellaneous ; Muscle Contraction - drug effects ; Muscle, Smooth - drug effects ; Muscle, Smooth - physiology ; Myocardial Contraction - drug effects ; Pharmacology. Drug treatments ; pyridinecarboxylates ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-05, Vol.41 (11), p.1827-1837</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</citedby><cites>FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2262068$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9599233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iqbal, Nadeem</creatorcontrib><creatorcontrib>Akula, Murthy R</creatorcontrib><creatorcontrib>Vo, Dean</creatorcontrib><creatorcontrib>Matowe, Wandikayi C</creatorcontrib><creatorcontrib>McEwen, Carol-Anne</creatorcontrib><creatorcontrib>Wolowyk, Michael W</creatorcontrib><creatorcontrib>Knaus, Edward E</creatorcontrib><title>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</description><subject>Animals</subject><subject>Atrial Function</subject><subject>Biological and medical sciences</subject><subject>Calcium Channel Agonists - chemical synthesis</subject><subject>Calcium Channel Agonists - chemistry</subject><subject>Calcium Channel Agonists - pharmacology</subject><subject>Calcium Channel Blockers - chemical synthesis</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Calcium Channels - drug effects</subject><subject>Cardiovascular system</subject><subject>congestive heart failure</subject><subject>Guinea Pigs</subject><subject>Heart Atria - drug effects</subject><subject>Hydrogen Bonding</subject><subject>Ileum - drug effects</subject><subject>Ileum - physiology</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscle, Smooth - drug effects</subject><subject>Muscle, Smooth - physiology</subject><subject>Myocardial Contraction - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>pyridinecarboxylates</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><recordid>eNqFkctuEzEUhkcIVEJhwQMgeUERlWLwfcbLKFxFUQstQmIzcuwzitMZT7A9qPNuPBxDEmWFxMqX7_Px0fmL4iklryhh9PWm0yWRTDf3ihmVjGBREXG_mBHCGGaK8YfFo5Q2hBBOGT8pTrTUmnE-K35fjyGvIfk0R1_7bDqI6DJ6CNlk34c5MsGhpWmtHzq0XJsQoEWfeze0O44WNvtfPntIqG_Qor0d290Thq_WECCvpzOdC_zGr0cXe8zmCjvf7QDmOPg8XQr8kmPUR6RwGlYp-zxkcJjh7Ri9G9tzLPdbH8CauOrvxul7SI-LB41pEzw5rKfFt3dvb5Yf8MXl-4_LxQU2ohQZA9CG0pWrBBGEg9QSaAWsoU5YoblSSuoKBFPGqRUjxlhitNDKlFC5Ult-WrzY193G_ucAKdedTxba1gToh1SXutKcE_ZfkZZKSqHkJJ7vRRv7lCI09Tb6zsSxpqT-G2l9jHRynx2KDqsO3NE8ZDjx5wdukjVtE02wPh01NuVPVDVpeK_5lOHuiE28rVXJS1nfXF3Xn8ov32W1_FGryT_b-8ametMPMUwj_kd7fwAX5cQj</recordid><startdate>19980521</startdate><enddate>19980521</enddate><creator>Iqbal, Nadeem</creator><creator>Akula, Murthy R</creator><creator>Vo, Dean</creator><creator>Matowe, Wandikayi C</creator><creator>McEwen, Carol-Anne</creator><creator>Wolowyk, Michael W</creator><creator>Knaus, Edward E</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QP</scope><scope>7X8</scope></search><sort><creationdate>19980521</creationdate><title>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</title><author>Iqbal, Nadeem ; Akula, Murthy R ; Vo, Dean ; Matowe, Wandikayi C ; McEwen, Carol-Anne ; Wolowyk, Michael W ; Knaus, Edward E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a474t-ee1f11bd840403e595e18e2f1d4c493666598e426ad6b20aac0a9496a7e8d79c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Atrial Function</topic><topic>Biological and medical sciences</topic><topic>Calcium Channel Agonists - chemical synthesis</topic><topic>Calcium Channel Agonists - chemistry</topic><topic>Calcium Channel Agonists - pharmacology</topic><topic>Calcium Channel Blockers - chemical synthesis</topic><topic>Calcium Channel Blockers - chemistry</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Calcium Channels - drug effects</topic><topic>Cardiovascular system</topic><topic>congestive heart failure</topic><topic>Guinea Pigs</topic><topic>Heart Atria - drug effects</topic><topic>Hydrogen Bonding</topic><topic>Ileum - drug effects</topic><topic>Ileum - physiology</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscle, Smooth - drug effects</topic><topic>Muscle, Smooth - physiology</topic><topic>Myocardial Contraction - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>pyridinecarboxylates</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iqbal, Nadeem</creatorcontrib><creatorcontrib>Akula, Murthy R</creatorcontrib><creatorcontrib>Vo, Dean</creatorcontrib><creatorcontrib>Matowe, Wandikayi C</creatorcontrib><creatorcontrib>McEwen, Carol-Anne</creatorcontrib><creatorcontrib>Wolowyk, Michael W</creatorcontrib><creatorcontrib>Knaus, Edward E</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iqbal, Nadeem</au><au>Akula, Murthy R</au><au>Vo, Dean</au><au>Matowe, Wandikayi C</au><au>McEwen, Carol-Anne</au><au>Wolowyk, Michael W</au><au>Knaus, Edward E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-05-21</date><risdate>1998</risdate><volume>41</volume><issue>11</issue><spage>1827</spage><epage>1837</epage><pages>1827-1837</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a − q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a − j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a − d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5−10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure−activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure−function relationships of calcium channels.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9599233</pmid><doi>10.1021/jm970529f</doi><tpages>11</tpages></addata></record> |
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ispartof | Journal of medicinal chemistry, 1998-05, Vol.41 (11), p.1827-1837 |
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subjects | Animals Atrial Function Biological and medical sciences Calcium Channel Agonists - chemical synthesis Calcium Channel Agonists - chemistry Calcium Channel Agonists - pharmacology Calcium Channel Blockers - chemical synthesis Calcium Channel Blockers - chemistry Calcium Channel Blockers - pharmacology Calcium Channels - drug effects Cardiovascular system congestive heart failure Guinea Pigs Heart Atria - drug effects Hydrogen Bonding Ileum - drug effects Ileum - physiology In Vitro Techniques Medical sciences Miscellaneous Muscle Contraction - drug effects Muscle, Smooth - drug effects Muscle, Smooth - physiology Myocardial Contraction - drug effects Pharmacology. Drug treatments pyridinecarboxylates Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Stereoisomerism Structure-Activity Relationship |
title | Synthesis, Rotamer Orientation, and Calcium Channel Modulation Activities of Alkyl and 2-Phenethyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates |
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