Malcolm Maccoss

Publications (4)10.6 Total impact

• Article: Synthesis and SAR of geminal substitutions at the C5' carbosugar position of pyrimidine-derived HCV inhibitors.

  Vishal A Verma, Randall Rossman, Frank Bennett, Lei Chen, Stephen Gavalas, Vinay Girijavallabhan, Yuhua Huang, Seong-Heon Kim, Aneta Kosinski, Patrick Pinto, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
  Bioorganic & medicinal chemistry letters 09/2012; 22(22):6967-73. · 2.65 Impact Factor
• Article: Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

  Frank Bennett, Hollis S Kezar, Vinay Girijavallabhan, Yuhua Huang, Regina Huelgas, Randall Rossman, Neng-Yang Shih, John J Piwinski, Malcolm MacCoss, Cecil D Kwong, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
  Bioorganic & medicinal chemistry letters 08/2012; 22(15):5144-9. · 2.65 Impact Factor
• Article: Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors.

  Vinay M Girijavallabhan, Carmen Alvarez, Frank Bennett, Lei Chen, Stephen Gavalas, Yuhua Huang, Seong-Heon Kim, Aneta Kosinski, Patrick Pinto, Razia Rizvi, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
  Bioorganic & medicinal chemistry letters 07/2012; 22(17):5652-7. · 2.65 Impact Factor
• Article: 5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

  Ashok Arasappan, Frank Bennett, Vinay Girijavallabhan, Yuhua Huang, Regina Huelgas, Carmen Alvarez, Lei Chen, Stephen Gavalas, Seong-Heon Kim, Aneta Kosinski, [......], Robert C Reynolds, Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge
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  ABSTRACT: Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
  Bioorganic & medicinal chemistry letters 03/2012; 22(9):3229-34. · 2.65 Impact Factor