Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors.
BACKGROUND
Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability.


RESULTS
We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation.


CONCLUSIONS
In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.
Rodgers
J D
JD
DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0500, USA. james.d.rodgers@dupontpharma.com
Lam
P Y
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Johnson
B L
BL
Wang
H
H
Li
R
R
Ru
Y
Y
Ko
S S
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Seitz
S P
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Trainor
G L
GL
Anderson
P S
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Klabe
R M
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Bacheler
L T
LT
Cordova
B
B
Garber
S
S
Reid
C
C
Wright
M R
MR
Chang
C H
CH
Erickson-Viitanen
S
S
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; C116353:DMP 850; C116354:DMP 851; D017320:HIV Protease Inhibitors; D014508:Urea