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<PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">8831757</PMID><DateCompleted><Year>1996</Year><Month>11</Month><Day>14</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0022-2623</ISSN><JournalIssue CitedMedium="Print"><Volume>39</Volume><Issue>20</Issue><PubDate><Year>1996</Year><Month>Sep</Month><Day>27</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J Med Chem</ISOAbbreviation></Journal><ArticleTitle>Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.</ArticleTitle><Pagination><StartPage>3908</StartPage><EndPage>3919</EndPage><MedlinePgn>3908-19</MedlinePgn></Pagination><Abstract><AbstractText>A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>White</LastName><ForeName>A D</ForeName><Initials>AD</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Purchase</LastName><ForeName>C F</ForeName><Initials>CF</Initials><Suffix>2nd</Suffix></Author><Author ValidYN="Y"><LastName>Picard</LastName><ForeName>J A</ForeName><Initials>JA</Initials></Author><Author ValidYN="Y"><LastName>Anderson</LastName><ForeName>M K</ForeName><Initials>MK</Initials></Author><Author ValidYN="Y"><LastName>Mueller</LastName><ForeName>S B</ForeName><Initials>SB</Initials></Author><Author ValidYN="Y"><LastName>Bocan</LastName><ForeName>T M</ForeName><Initials>TM</Initials></Author><Author ValidYN="Y"><LastName>Bousley</LastName><ForeName>R F</ForeName><Initials>RF</Initials></Author><Author ValidYN="Y"><LastName>Hamelehle</LastName><ForeName>K L</ForeName><Initials>KL</Initials></Author><Author ValidYN="Y"><LastName>Krause</LastName><ForeName>B R</ForeName><Initials>BR</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>P</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Stanfield</LastName><ForeName>R L</ForeName><Initials>RL</Initials></Author><Author ValidYN="Y"><LastName>Reindel</LastName><ForeName>J F</ForeName><Initials>JF</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Med Chem</MedlineTA><NlmUniqueID>9716531</NlmUniqueID><ISSNLinking>0022-2623</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C101723">2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxyphenyl)acetamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C101724">2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxyphenyl)acetamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000081">Acetamides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000924">Anticholesteremic Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007555">Isoxazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>97C5T2UQ7J</RegistryNumber><NameOfSubstance UI="D002784">Cholesterol</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.1.26</RegistryNumber><NameOfSubstance UI="D002785">Sterol O-Acyltransferase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000081" MajorTopicYN="N">Acetamides</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000307" MajorTopicYN="N">Adrenal Gland Diseases</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000924" MajorTopicYN="N">Anticholesteremic Agents</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001161" MajorTopicYN="N">Arteriosclerosis</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002784" MajorTopicYN="N">Cholesterol</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004285" MajorTopicYN="N">Dogs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004791" MajorTopicYN="N">Enzyme Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006168" MajorTopicYN="N">Guinea Pigs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007555" MajorTopicYN="N">Isoxazoles</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008099" MajorTopicYN="N">Liver</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011817" MajorTopicYN="N">Rabbits</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002785" MajorTopicYN="N">Sterol O-Acyltransferase</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists &amp; inhibitors</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>1996</Year><Month>9</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2001</Year><Month>3</Month><Day>28</Day><Hour>10</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>1996</Year><Month>9</Month><Day>27</Day><Hour>0</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">8831757</ArticleId><ArticleId IdType="doi">10.1021/jm9604033</ArticleId><ArticleId IdType="pii">jm9604033</ArticleId></ArticleIdList></PubmedData></PubmedArticle></PubmedArticleSet>