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Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution.

Abstract
Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.
AuthorsM J Genin, T J Poel, P D May, L A Kopta, Y Yagi, R A Olmsted, J M Friis, R L Voorman, W J Adams, R C Thomas, D L Romero
JournalJournal of medicinal chemistry (J Med Chem) Vol. 42 Issue 20 Pg. 4140-9 (Oct 07 1999) ISSN: 0022-2623 [Print] United States
PMID10514284 (Publication Type: Journal Article)
Chemical References
  • Aminopyridines
  • Anti-HIV Agents
  • PNU 103657
  • Piperidines
  • Recombinant Proteins
  • Reverse Transcriptase Inhibitors
  • Sulfonamides
Topics
  • Administration, Oral
  • Aminopyridines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Animals
  • Anti-HIV Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Biological Availability
  • Cells, Cultured
  • In Vitro Techniques
  • Injections, Intravenous
  • Male
  • Microsomes, Liver (drug effects, enzymology)
  • Piperidines (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins (antagonists & inhibitors)
  • Reverse Transcriptase Inhibitors (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, chemistry, pharmacokinetics, pharmacology)

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