Aminodiol HIV protease inhibitors. 1. Design, synthesis, and preliminary SAR
A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a resul...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-06, Vol.37 (12), p.1758-1768 |
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| container_end_page | 1768 |
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| container_issue | 12 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Barrish, J C Gordon, E Alam, M Lin, P F Bisacchi, G S Chen, P Cheng, P T Fritz, A W Greytok, J A Hermsmeier, M A |
| description | A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h). |
| doi_str_mv | 10.1021/jm00038a005 |
| format | Article |
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Design, synthesis, and preliminary SAR</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Barrish, J C ; Gordon, E ; Alam, M ; Lin, P F ; Bisacchi, G S ; Chen, P ; Cheng, P T ; Fritz, A W ; Greytok, J A ; Hermsmeier, M A</creator><creatorcontrib>Barrish, J C ; Gordon, E ; Alam, M ; Lin, P F ; Bisacchi, G S ; Chen, P ; Cheng, P T ; Fritz, A W ; Greytok, J A ; Hermsmeier, M A</creatorcontrib><description>A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. 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Design, synthesis, and preliminary SAR</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).</description><subject>AIDS/HIV</subject><subject>Amino Alcohols - chemical synthesis</subject><subject>Amino Alcohols - pharmacology</subject><subject>Animals</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - pharmacology</subject><subject>Cells, Cultured</subject><subject>Drug Design</subject><subject>HIV - drug effects</subject><subject>HIV - enzymology</subject><subject>HIV Protease - metabolism</subject><subject>HIV Protease Inhibitors - chemical synthesis</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>HIV-1 - drug effects</subject><subject>HIV-2 - drug effects</subject><subject>Humans</subject><subject>Male</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>Swine</subject><issn>0022-2623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotj0lPwzAUhH0AlVI4cUbyiVMTnu3YOMeoLK0UCYntGnkLdZWNODn032NET_P05tNoBqEbAikBSu4PLQAwqQD4GVoCUJpQQdkFugzh8GcRyhZoISObE7FEZdH6rre-b_B294WHsZ-cCg77bu-1n_oxpJik-NEF_92tcTh20z7eYY1VZyPuGh8D1HjE78XbFTqvVRPc9UlX6PP56WOzTcrXl92mKJOBgpgSIQ2nnCmoLViTZ1oakikqLSjFDNHECadzYSirmdWWZ_FpDWjHMg5ZrdkK3f3nxro_swtT1fpgXNOozvVzqB4EzwmVPIK3J3DWrbPVMPo2dq1O89kv6jBZWg</recordid><startdate>19940610</startdate><enddate>19940610</enddate><creator>Barrish, J C</creator><creator>Gordon, E</creator><creator>Alam, M</creator><creator>Lin, P F</creator><creator>Bisacchi, G S</creator><creator>Chen, P</creator><creator>Cheng, P T</creator><creator>Fritz, A W</creator><creator>Greytok, J A</creator><creator>Hermsmeier, M A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19940610</creationdate><title>Aminodiol HIV protease inhibitors. 1. 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Design, synthesis, and preliminary SAR</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>1994-06-10</date><risdate>1994</risdate><volume>37</volume><issue>12</issue><spage>1758</spage><epage>1768</epage><pages>1758-1768</pages><issn>0022-2623</issn><abstract>A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).</abstract><cop>United States</cop><pmid>8021916</pmid><doi>10.1021/jm00038a005</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 1994-06, Vol.37 (12), p.1758-1768 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | AIDS/HIV Amino Alcohols - chemical synthesis Amino Alcohols - pharmacology Animals Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Cells, Cultured Drug Design HIV - drug effects HIV - enzymology HIV Protease - metabolism HIV Protease Inhibitors - chemical synthesis HIV Protease Inhibitors - pharmacology HIV-1 - drug effects HIV-2 - drug effects Humans Male Rats Rats, Sprague-Dawley Structure-Activity Relationship Swine |
| title | Aminodiol HIV protease inhibitors. 1. Design, synthesis, and preliminary SAR |
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