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.
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Authors | M 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 42
Issue 20
Pg. 4140-9
(Oct 07 1999)
ISSN: 0022-2623 [Print] United States |
PMID | 10514284
(Publication Type: Journal Article)
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Chemical References |
- Aminopyridines
- Anti-HIV Agents
- PNU 103657
- Piperidines
- Recombinant Proteins
- Reverse Transcriptase Inhibitors
- Sulfonamides
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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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