ABSTRACT
Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemistry , Phosphodiesterase 4 Inhibitors , Quinolines/chemistry , Administration, Oral , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Macaca fascicularis , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Solubility , Structure-Activity RelationshipSubject(s)
Fibrinolytic Agents/pharmacology , Piperazines/pharmacology , Piperidines/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Membrane Glycoproteins/antagonists & inhibitors , Administration, Oral , Animals , Blood Platelets/drug effects , Callithrix , Fibrinolytic Agents/administration & dosage , Humans , Piperazines/administration & dosage , Piperidines/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Structure-Activity RelationshipABSTRACT
The following 5-(2-substituted vinyl)-6-aza-2'-deoxyuridines were synthesized: (E)-5-(2-bromovinyl) (2) (6-aza-BVDU), 5-(2-bromo-2-fluorovinyl) (a mixture of E and Z isomers) (3), (E)-5-(2-chlorovinyl) (4), (E)-5-[2-(methylthio)vinyl] (5), 5-(2,2-dibromovinyl) (6), and 5-(3-furyl) (7). The synthesis of 2-6 utilized Wittig-type reactions on 5-formyl-1-(2'-deoxy-3', 5'-di-O-p-toluoyl-beta-D-erythro-pentofuranosyl)-6-azauracil (16). 6-Aza-BVDU (and its alpha-anomer) was also synthesized from (E)-5-(2-bromovinyl)-6-azauracil (12) by using standard deoxyribosidation methodology. Compound 7 was prepared from 5-(3-furyl)-6-azauracil (33) via a ribosidation/deoxygenation sequence. An attempt to prepare the corresponding 5-(2,2-difluorovinyl) analogue afforded instead a mixture of the 5-[(2,2-difluoro-2-methoxy)ethyl] and 5-(2,2,2-trifluoroethyl) derivatives 29 and 30. Compounds 2-7, 29, and 30 were tested for in vitro activity against herpes simplex virus types 1 and 2 (HSV-1, HSV-2). 6-Aza-BVDU (2) exhibited ID50s of 8 micrograms/mL vs. HSV-1 and 190 micrograms/mL vs. HSV-2. BVDU (1) had ID50s of 0.015 and 1.6 micrograms/mL against HSV-1 and HSV-2, respectively. Compound 4 showed a similar profile of activity, but the other analogues were either weakly active or inactive.
