J. F. Miller et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3496–3500
Table 2. In vivo pharmacokinetic parameters for 12a and 12b
3499
(EP13 and D545701)8 were determined in an MT4 cell
line.9
Entry
Species
Dose
(mg/kg)
IV clearance
(mL/h/kg)
t1/2
% F
(h)
The primary amine derivatives 10a–c show a clear in-
crease in wild-type and mutant antiviral activity upon
extending the P1 chain from n = 1 to n = 3. This trend is
consistent with a new side chain interaction which is
strongest for n = 3. However, in the absence of enzyme
inhibitory activities10 or X-ray crystallographic data sup-
porting a new interaction, the strength of this inference is
limited. Clearly, factors beyond intrinsic enzyme activity,
such as cell penetration and protein binding, influence the
observed trends in cellular antiviral activities.
12b
12b
12a
12a
12a
Rat
1.0
0.5
1.0
0.5
0.5a
43
30
55
68
nd
0.2
1.1
1.6
nd
ꢁ3
ꢁ1
ꢁ1
0
Dog
Rat
Dog
Dog
0.6
33b
a Co-administered with 4 mg/kg ritonavir.
b Calculated by dividing the ritonavir-boosted oral AUC by the non-
boosted IV AUC.
potent antiviral activity and in many cases inverse anti-
viral resistance profiles. As a class, the methyl carba-
mates 12a–c are the most potent with mutant antiviral
potencies of up to 35 times that of the currently market-
ed PI atazanavir. In addition, they show significant
improvements in mutant antiviral activities versus our
earlier generation arylsulfonamide series (i.e, compound
1). Structural studies aimed toward elucidating any po-
tential new enzyme–inhibitor interactions and the origin
of the inverse resistance behavior are currently in pro-
gress and will be reported in due course.
Acetyl derivatives 11a–c are in general more potent than
the analogous primary amines and they show a striking
inverse resistance profile with approximately threefold
increases in mutant activities versus wild-type. This in-
verse resistance behavior, often referred to as Ôhypersus-
ceptibilityÕ11, compares favorably to the threefold and
>25-fold decrease in D545701 activities for atazanavir
and lopinavir, respectively. Methyl carbamates 12a–c
comprise the most potent class of molecules in the series
with single digit nanomolar IC50s for all three virus
strains tested. Interestingly, there appears to be no
dependence of potency on the length of the P1 tether
for the carbamate derivatives. The impressive potencies,
along with the absence of a chain length SAR, suggest
that their activities are probably more a function of
physiochemical parameters than any specific P1 side
chain binding interactions. Perhaps the methyl carba-
mate moiety imparts favorable polarity properties lead-
ing to an enhancement in cell penetration.
References and notes
1. (a) Palella, F. J.; Delaney, K. M.; Moorman, A. C.;
Loveless, M. O.; Fuhrer, J.; Satten, G. A.; Aschman, D. J.;
Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853; (b)
Hammer, S. M.; Squires, K. E.; Hughes, M. D.; Grimes, J.
M.; Demeter, L. M.; Currier, J. S.; Eron, J. J.; Feinberg, J.
E.; Balfour, H. H.; Deyton, L. R.; Chodakewitz, J. A.;
Fischl, M. A.; Phair, J. P.; Pedneault, L.; Nguyen, B. Y.;
Cook, J. C. N. Engl. J. Med. 1997, 337, 725.
2. (a) Boden, D.; Markowitz, M. Antimicrob. Agents Che-
mother. 1998, 42, 2775; (b) Tisdale, M.; Myers, R. E.;
Maschera, B.; Parry, N. R.; Oliver, N. M.; Blair, E. D.
Antimicrob. Agents Chemother. 1995, 39, 1704.
3. Miller, J. F.; Furfine, E. S.; Hanlon, M. H.; Hazen, R. J.;
Ray, J. A.; Robinson, L.; Samano, V.; Spaltenstein, A.
Bioorg. Med. Chem. Lett. 2004, 14, 959.
4. Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.;
Wang, X.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P.
Tetrahedron Lett. 1997, 18, 3175.
5. Tao, E.V.P.; Miller, W.D. U.S. Patent 5,387,681, 1995.
6. Ghosh, A. K.; Kincaid, J. F.; Walters, D. E.; Chen, Y.;
Chaudhuri, N. C.; Thompson, W. J.; Culberson, C.;
Fitzgerald, P. M. D.; Lee, H. Y.; McKee, S. P.; Munson,
P. M.; Duong, T. T.; Darke, P. L.; Zugay, J. A.; Schleif,
W. A.; Axel, M. G.; Lin, J.; Huff, J. R. J. Med. Chem.
1996, 39, 3278.
7. The wild-type virus HXB2 was derived from the pHXB2-
D molecular clone For further details see: Fischer, A. G.;
Collati, E.; Ratner, L.; Gallo, R. C.; Wong-Stall, F.
Nature (London) 1985, 316, 262.
8. The EP13 and D545701 strains are engineered viruses
containing mutations associated with clinically observed
PI therapy failure in patients exposed to multiple protease
inhibitors. They contain the following mutations relative
to the consensus sequence of wild-type virus. EP13:
protease—M46I, L63P, A71V, V82F/L, I84V; no reverse
transcriptase mutations. D545701: protease—L10I, L19Q,
K20R, E35D, M36I, S37N, M46I, I50V, I54V, I62V,
L63P, A71V, V82A, L90M; reverse transcriptase—E28K,
A comparison of monomethyl urea derivatives 13a–c to
dimethyl ureas 14a–c is interesting. The monomethyl
compounds show a consistent chain length SAR similar
to that observed for primary amines 10a–c and aceta-
mides 11a–c. In contrast, the dimethyl derivatives dis-
play a relatively flat chain length SAR and they are, as
a class, more potent than the analogous monomethyl
compounds. The methanesulfonyl derivatives 15a–c
show a chain length SAR against the wild-type virus
that is consistent with compounds 10, 11, and 13; how-
ever, the activity trends against the two mutant viruses
are rather ill-defined.
Table 2 summarizes the in vivo pharmacokinetic analy-
sis of methyl carbamate derivatives 12a and 12b. Both
compounds possess negligible oral bioavailability in
both rat and dog. However, when 12a was co-adminis-
tered with the potent cytochrome P450 inhibitor ritona-
vir,
a dramatic increase from 0% to 33% oral
bioavailability was achieved. Poor oral bioavailability
is one of the general shortcomings of the HIV protease
drug class. This can be effectively offset by ÔboostingÕ sys-
temic drug exposures via ritonavir co-administration
and in fact this has become standard clinical practice
(e.g., co-formulation of ritonavir with lopinavir in the
commercial preparation of Kaletra).12
In summary, we have discovered a novel series of P1
chain-extended arylsulfonamide HIV-PIs that show very