Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution.
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.
Genin
M J
MJ
Medicinal Chemistry Research, Infectious Diseases Research, Discovery Technologies, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Poel
T J
TJ
May
P D
PD
Kopta
L A
LA
Yagi
Y
Y
Olmsted
R A
RA
Friis
J M
JM
Voorman
R L
RL
Adams
W J
WJ
Thomas
R C
RC
Romero
D L
DL
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000631:Aminopyridines; D019380:Anti-HIV Agents; C122060:PNU 103657; D010880:Piperidines; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides