Indinavir analogues with blocked metabolism sites as HIV protease inhibitors with improved pharmacological profiles and high potency against PI-resistant viral strains

Article abstract of DOI:10.1016/S0960-894X(02)00424-9

Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.

Full text of DOI:10.1016/S0960-894X(02)00424-9

Bioorganic & Medicinal ChemistryLetters 12 (2002) 2419–2422
Indinavir Analogues with Blocked Metabolism Sites as HIV
Protease Inhibitors with Improved Pharmacological Profiles
and High Potency Against PI-Resistant Viral Strains
Yuan Cheng,a,* Fengqi Zhang,a Thomas A. Rano,a Zhijian Lu,a William A. Schleif,b
Lori Gabryelski,b David B. Olsen,c Mark Stahlhut,c Carrie A. Rutkowski,c Jiunn H. Lin,d
Lixia Jin,d Emilio A. Emini,b Kevin T. Chapmana and James R. Tataa
aDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
bDepartment of Viral Vaccine Research, Merck Research Laboratories, West Point, PA 19486, USA
cDepartment of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
dDepartment of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
Received 26 March 2002; accepted 17 May2002
Abstract—Indinavir analogues with blocked metabolism sites show highlyimproved pharmacokinetic profiles in animals. The cis-
aminochromanol substituted analogues exhibited excellent potencyagainst both the wild-type (NL4-3) virus and protease inhibitor-
resistant HIV strains. # 2002 Elsevier Science Ltd. All rights reserved.
In the past decade, extensive research has focused on
identifying HIV protease (PR) inhibitors for the treat-
ment of human immunodeficiencyvirus (HIV-1) infec-
tion.1 Several HIV protease inhibitors, including
Indinavir, have been approved bythe US Food and
Drug Administration as keytherapeutic agents for the
treatment of HIV infection and AIDS.1,2 Although
these drugs represent a major advance in the manage-
ment of HIV disease, theysuffer, to some extent, from
first-pass metabolism and/or food restrictions. In addi-
tion, a number of patients develop resistance to multiple
protease inhibitors through viral mutations.3 There are
two approaches to develop drugs that are efficacious
against resistant mutants: one is to improve pharmaco-
kinetic profiles byblocking the metabolic sites and
another is to improve potencyof HIV PR inhibitors. In
an effort to develop a second-generation drug with bet-
ter pharmacokinetic parameters and improved activity
against resistant mutants, we launched an investigation
to modifythe Indinavir class of protease inhibitors by
The benzylic position of the aminoindanol moiety in the
0
P2 position as well as the pyridine nitrogen and the
methylene linker in P3 have been identified as the major
metabolic sites in Indinavir (Fig. 1).4 As such we first
incorporated a gem-dimethylpyridyl substituent into the
P3 position. The resulting compound, 1, had a Cmax
more than 20 times greater than that of Indinavir when
dosed orallyin rats. The t1/2 of 1 is more than twice as
long as Indinavir in both rats and dogs. Encouraged by
these results, we reviewed historical data and found that
pyridylfuran derivative 2 prepared during the initial
0
varying the P2 and P3 moieties.
*Corresponding author. Fax: +1-732-594-9556; e-mail: yuan_cheng@
merck.com
Figure 1. Denotes metabolism byCYP3A4.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00424-9

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Y. Cheng et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2419–2422
protease program had reasonable potencyand bio-
availability. We were interested in combining the gem-
dimethyl concept with the pyridylfuran of 2 and
additionallyreplacing the aminoindanol to address the
metabolic liabilityof the benzylic position with a more
robust aminochromanol moiety(Fig. 2). In this
communication, we report the successful execution of
this strategythat resulted in compounds with improved
pharmacokinetic profiles and increased potencyagainst
PI-resistant viral strains.
TBSOTf affording, after hydrolysis of the TBS ester
with THF/H2O, acid 9. Aminoindanol 10 was coupled
to acid 9 using HBTU and HOBt to afford 11. The
iodine was removed byhdyrogenation with Pd/C in
ethanol and the TBS group was removed with HF/pyr-
idine to give 3.
In order to block the metabolic site on the aminoinda-
nol, we synthesized aminochromanol8 as illustrated in
Scheme 2. 4-Chromanone was brominated with bro-
mine in CH2Cl2. Although a mixture of mono- and di-
bromo products at a-ketone position was obtained, the
di-bromo product 12 could be quantitativelyconverted
The synthetic strategy for incorporation of the gem-
dimethylpyridyl substituent is shown in Scheme 1. We
started with intermediate 55 that was first treated with
TFA to remove the Boc protecting group. Copper
mediated alkylation with 3-chloro-3-methyl-butyne gave
intermediate 6.6 Reaction of 6 with diiodo-hydroxy-
pyridine 7 under Castro–Stevens conditions7 resulted in
smooth cyclization to provide pyridylfuran lactone 8.
The lactone in intermediate 8 was opened with LiOH in
dioxane and the hydroxyl group was protected with
to mono-bromo product 13 bytreatment with Na SO3
2
in wet acetic acid. Bromoketone 13 was reduced with
NaBH4 to afford bromo alcohol 14. Using Ritter reac-
tion9 conditions, 14 was converted to amino alcohol
15.10 The desired 3S,4S enantiomer 16 was isolated by
crystallization from ethanol with (S)-mandelic acid.
Coupling of aminochromanol 16 to acid 9 provided
compound 4.
Figure 2. Approaches to block metabolism sites of pyridylfuran derivative.
Scheme 1. Reagents and conditions: (a) TFA/CH2Cl2 30%, 1 h; (b) 3-chloro-3-methyl-1-butyne, Cu, CuCl, Et3N, THF; (c) CuI, N-ethylpiperidine,
DMF; (d) LiOH, dioxane; (e) TBSOTf, DIEA, THF; (f) H2O/THF 1:1; (g) HBTU, HOBt, DIEA, DMF; (h) H2, Pd/C 10%, ethanol; (i) HF/pyri-
dine, THF.

Y. Cheng et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2419–2422
Table 1. In vitro potencyagainst wild-type HIV virus
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Compd
Enzyme inhibition
IC50 (nM)
Viral spread
CIC95 (nM)
Indinavir
0.59
1.16
0.23
0.15
0.075
50
50
15
15
1
2
3
4
<8
Table 2. In vitro potencyof compounds against HIV mutant strains
Compd
Viral spread data (CIC95, NM)
WT
4X Virus
K-60C
Q-60C
V-18C
Indinavir
3
4
50.5
15
<8
500
625
31
>3000
>1000
500
>1000
>1000
250
1500
>1000
250
Table 3. Pharmacokinetics in dogs
Compd
Dose
(po dose mpk)
Cmax
(mM)
AUC
(mM h)
F
(%)
t1=2
(min)
Scheme 2. Synthesis of (3S,4S)-aminochromanol.
Indinavir
3
4
Dog (10)
Dog (5)
Dog (5)
11.4
16.6
8.85
12.5
14.1
7.43
71.6
44.3
81
38
47
62.4
Compounds 1, 3, and 4 were tested along with Indinavir
for their abilityto inhibit cleavage of a substrate bythe
wild-type HIV-1 protease enzyme and to inhibit the
spread of viral infection in MT4 human T-lymphoid
cells infected bythe NL4-3 virus (Table 1). The gem-
dimethyl derivative of Indinavir, 1, was as potent
as Indinavir in viral spread assay, although it was about
2-fold less active in the enzyme inhibition assay. The
gem-dimethyl pyridylfuran derivative 3 exhibited the
same potencyas its unsubstituted analogue 2 in both the
enzyme inhibition assay and viral spread assay. These
results demonstrate that compounds with the gem-
dimethyl substitution retain the high potency of their
unsubstituted counterparts. Gratifyingly, the amino-
chromanol derivative 4 showed enhanced potencyover
the aminoindanol derivative 3 in the viral spread assay
(<8 nM vs 15 nM).
improved values. The half lives (t1/2) of compounds 3
and 4 were also improved over that of Indinavir (47, 62,
and 38 min, respectively).
In summary, we have demonstrated that we can
improve the pharmacokinetic profile of Indinavir ana-
logues byblocking sites of metabolism. In addition
substitution of aminoindanol with aminochromanol
afforded compounds with greater potencyagainst both
the wild-type (NL4-3) virus and PI-resistant HIV
strains.
Encouraged bythese findings we further investigated
the impact of the aminochromanol substituent on the
potencyof Indinavir analogues bytesting a set of com-
pounds against PI-resistant viral constructs (Table 2).
The viral constructs used in the viral spread assaywere
engineered from clinical viral isolates of patients infec-
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