AL-12182, a novel 11-oxa prostaglandin analog with topical ocular hypotensive activity in the monkey

Article abstract of DOI:10.1016/j.bmcl.2004.06.037

A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester prodrug of the

Full text of DOI:10.1016/j.bmcl.2004.06.037

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4525–4528
AL-12182, a novel 11-oxa prostaglandin analog with
topical ocular hypotensive activity in the monkey
Robert D. Selliah, Mark R. Hellberg, Najam A. Sharif, Marsha A. McLaughlin,
Gary W. Williams, Daniel A. Scott, David Earnest, Karen S. Haggard,
W. Dennis Dean, Pete Delgado, Michael S. Gaines, Raymond E. Conrow and
Peter G. Klimko*
Alcon Research, Ltd, Pharmaceutical Products Research, 6201 South Freeway, MS R2-39 Fort Worth, TX 76134, USA
Received 5 May 2004; revised 11 June 2004; accepted 12 June 2004
Available online 2 July 2004
Dedicated to the memory of Dr. Tai-Lee Ke, our esteemed colleague and friend
Abstract—A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds
having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester
prodrug of the potent agonist 13, lowered intraocular pressure in the monkey by 40% accompanied by minimal conjunctival
hyperemia in the rabbit. AL-12182 was synthesized on multigram scale starting with
ꢀ 2004 Elsevier Ltd. All rights reserved.
D-sorbitol.
Glaucoma, a heterogeneous family of optic neuropa-
thies, is a leading cause of blindness in the developed
world. Although the disease process and its causative
factors are not completely understood, elevated intra-
ocular pressure (IOP) is an important risk factor for
loss of visual field due to optic nerve damage.1
Endogenous prostaglandins (PGs) and their prodrugs,
such as PGF2a isopropyl ester, reduce IOP in man but
also cause conjunctival hyperemia, foreign-body sensa-
tion, and ocular pain.2 The development of prodrugs of
potent, selective synthetic prostaglandin FP receptor
agonists as clinically effective IOP-lowering agents de-
void of many of these side effects has been an important
advance in the treatment of glaucoma.3 Thus latano-
prost, the related D13 (E) ethyl amide bimatoprost, and
the aryloxy-terminated compound travoprost4 are
prostaglandin analogs that have been introduced into
clinical practice as active ingredients of topical IOP-
lowering medications.
Further investigations have led to the exploration of
compounds having an 11-oxa (i.e., tetrahydrofuran)
structure instead of the cyclopentane core of endoge-
nous PGs. Others have reported the synthesis of 11-oxa
PGF2a (3, Table 1) and of omega-chain modified ana-
logs,5–8 for example, the PGF2a analog 17 and the PGE2
analogs 2.8 One report noted that 3 and its C9 epimer
lacked FP receptor-linked bioactivity in an ex vivo
smooth muscle contraction assay.5 To the best of our
knowledge no other biological data have been reported
for 11-oxa prostaglandins, although typical PG-like
systemic activities are suggested in patents.8;9 We now
report the results of in vitro and in vivo biological
Keywords: 11-Oxa prostaglandin; Glaucoma.
* Corresponding author. Tel.: +1-817-551-6932; fax: +1-817-615-4696;
e-mail: peter.klimko@alconlabs.com
Present address: Prolexys Pharmaceuticals, Department of Medicinal
Chemistry, 2150 W. Dauntless Ave., Salt Lake City, UT 84116, USA.
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.037

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R. D. Selliah et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4525–4528
Table 1. FP receptor binding affinity and functional response
Compound
X
A
B
R
Ki SEM,a nM
EC50 SEM,a nM
(% response)
3b
––
––
OH
H
H
––
––
6700 620
>10,000
640 84
2380 214 (64)
>10,000
4c
OH
H
5
ZACH@CHCH2
ZACH@CHCH2
ZACH@CHCH2
ZACH@CHCH2
ZACH@CHCH2
ZACH@CHCH2
ZACH2CH@CH
ZACH2CH@CH
ZACH2CH@CH
ZACH2CH@CH
ZACH2CH@CH
ZACH2CH@CH
––
OH
H
H
293 45 (67)
573 201 (49)
58 18 (84)
194 19 (67)
187 35 (74)
899 101 (43)
57 2 (83)
6
OH
H
H
Cl
2800 560
890 270
7300 3000
3100 1400
>10,000
7
OH
H
8
OH
H
Cl
9
10
OH
H
CF3
CF3
H
OH
H
11
12
OH
H
330 100
5100 2800
147 36
OH
H
H
Cl
252 6 (59)
23 3 (88)
13
14
OH
H
OH
H
Cl
820 410
350 140
9900 180
129 12
249 66 (71)
67 35 (88)
781 2 (61)
24.5 0.92 (92)
34.4 5.2 (75)
2.7 0.28 (100)
15
16
OH
H
CF3
CF3
––
OH
––
PGF2a
Latanoprost acid
Travoprost acid
––
––
––
––
––
––
––
––
92 14
52 2
––
a SEM ¼ Standard error of the mean.
b 3 ¼ 11-oxa-PGF2a
.
c 4 ¼ 15-epi-11-oxa-PGF2a
.
studies on a series of 11-oxa PGs culminating in the
discovery of AL-12182, a highly effective topical ocular
hypotensive agent in the monkey.
D4 modification on FP receptor response. In the present
11-oxa PG series this D4 modification increased FP
receptor binding affinity and functional potency in two
cases (13 vs 7 and 15 vs 9), while in one case (11 vs 5) little
effect was observed. Acid 13 was comparable in potency
and efficacy to PGF2a and latanoprost acid.16
The favorable in vitro profiles of acids 7 and 13 led to
the evaluation of their isopropyl ester prodrugs 17 and
AL-12182 in three animal models (Table 2). Conjuncti-
val hyperemia (red eye), a side effect, was studied in New
Zealand Albino rabbits. RCH15 denotes the dose esti-
mated to elicit 15% incidence of hyperemia over the 4 h
course of the study.4 As a preliminary assay of topical
ocular potency and thus potential IOP-lowering effec-
tiveness, the ability of a compound to constrict the cat
pupil over time was measured and is expressed as an
ED5 value,4 indicating the dose estimated to produce a 5
unit (mm h) difference in pupil diameter between the
dosed and control eye. Acute IOP-lowering efficacy was
measured in conscious ocular hypertensive cynomolgous
monkeys.4 The IOP reductions in Table 2 are the maxi-
ma observed for the indicated doses.
Table 1 summarizes our evaluation of the acids 3–16 for
binding to an FP receptor expressed in bovine corpus
luteum (Ki),10 and for functional potency (EC50 ¼ effective
concentration necessary for a compound to attain 50% of
its maximal response) and efficacy via stimulation of FP
receptor-linked phosphoinositide turnover in Swiss 3T3
mouse fibroblast cells.11 The configuration of the omega
chain carbinyl stereocenter was provisionally assigned
based on EC50 values in the FP functional assay, with the
more potent diastereomer being designated as that having
A ¼ OH, B ¼ H.12 The standards PGF2a, latanoprost
acid, and travoprost acid are included for comparison.
Based on its superior in vivo profile, AL-12182 was
selected for large-scale synthesis as a potential clinical
candidate. We had prepared compounds 3–16 on ca.
10 mg scale from the known nonracemic pro-11-oxa
analog of Corey lactone.5–7 In turn, we had obtained this
intermediate from D
-glucose,7 but found that the req-
uisite anomeric deoxygenation sequences did not scale
up well. We therefore adopted an alternative route
reported by Hanessian et al.5 that uses inexpensive
Compounds 11–16 feature a D4 double bond in the alpha
chain.13–15 Application of this structural perturbation to
PGF2a inhibited metabolic degradation in the monkey.14
We are unaware of any prior report on the effect of this

R. D. Selliah et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4525–4528
4527
Table 2. Rabbit, cat, and monkey data
a
Compound
RCH15
CPD,b ED5
MIOP,c % change (dose)
17
AL-12182
30 lg
30 lg
<0.1 lg
1.8 lg
3 lg
0.8 lg
0.2 lg
0.03 lg
0.13 lg
0.014 lg
)15% (30 lg)
)40% (3 lg)
)38% (1 lg)
)27% (3 lg)
)29% (0.3 lg)
PGF2a isopropyl ester
Latanoprost
Travoprost
a RCH15 ¼ Dose estimated to elicit conjunctival hyperemia in 15% of the tested rabbits over 4 h.
b CPD ¼ Cat pupil diameter constriction.
c MIOP ¼ Monkey intraocular pressure.
D
-sorbitol as the starting material and proceeds via
tetrahydrofuran ester 22. Our process research efforts
migration. By means of this detour, crystalline 21 could
be secured without resort to chromatography. Moffatt
oxidation of 21, Wittig condensation and hydrogenation
of the resulting enoate gave 22 efficiently, as reported.5
led to expedited procedures17 by which we prepared 3 kg
of 22. Thus the acid-catalyzed dehydration18 of
D-sor-
bitol (4 kg scale) was conducted in a concentrated melt
followed by a nonaqueous workup to afford crystalline
1,4-anhydro-D-sorbitol (18) in 47% yield. The two-step
On small scale, the synthesis of the D4 compounds
11–16 was accomplished by one-carbon extension of a
pro-C6 aldehyde or lactol core structure using
Ph3P@CHOMe.13–15 Two alternative sequences, consid-
ered to be more favorable for scaleup, were evaluated
for advancing 22 to AL-12182 on multigram scale.
conversion5 of 18 to silyl ether 21 proved impractical on
kilo scale due to nonoptimal discrimination among the
hydroxyl groups, resulting in the formation of regio-
isomeric contaminants. In contrast, the conversion of 18
to ortho ester 1919 proceeded cleanly. Silylation of 19
was followed by stirring with Amberlyst 15 resin in
MeOH–H2O to yield triol 20 without evidence of silyl
In the first sequence, ester 22 was transformed to mes-
ylate 23, and the derived iodide (8 g scale) was reacted
Scheme 1. (DPS ¼ diphenyl-t-butylsilyl). Reagents and conditions: (a) (1) LiAlH4, Et2O, 0ꢁ (90%); (2) MsCl, Et3N, CH2Cl2, 0ꢁ (98%). (b) To give 24:
(1) NaI, Me2CO, D (86%); (2) 4-pentynoic acid, LiNH2, NH3, )33ꢁ; add iodide in THF; quench with NH4Cl; fi pH 3; CH2N2, Et2O (73%). (3) H2,
Pd(BaSO4), py, )25ꢁ (86% of a 96:4 Z/E mixture, 0.5% overreduction, 6% recovered alkyne). (c) (1) 24, H5IO6, EtOAc, 4 A MS (91%); (2)
(MeO)2P(O)CH2COCH2OC6H4Cl-m, Et3N, LiCl, THF, 0ꢁ (69%); (3) ())-Ipc2BCl, THF, )15 to 0ꢁ (91% of an 88:12 R/S mixture); (4) Ti(O–i-Pr)4,
i-PrOH, D (100%). (d) (1) NaCN, Me2SO, 45ꢁ (95%); (2) i-Bu2AlH/hexane, toluene, )65ꢁ; 10% aq HOAc, fi 0ꢁ (94%). (e) To give 27: Ph3Pþ
(CH2)3CO2–i-Pr, Brꢀ, NaN(SiMe3)2, THF, 20ꢁ; add 26 in toluene, )68ꢁ, then fi )20ꢁ (85% of a 97:3 Z/E mixture). (f) (1) 27, H5IO6, i-PrOAc (99%);
(2) Ph3P@CHCOCH2OC6H4Cl-m, HOAc, CH2Cl2 (90%); (3) ())-Ipc2BCl/heptane, THF, )45ꢁ (75% of a 93:7 R/S mixture, after desilylation).

4528
R. D. Selliah et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4525–4528
with LiCBC(CH2)2CO2Li in liquid NH3.20 The product
was esterified and then semihydrogenated. Chromato-
graphy at this stage separated residual alkynyl ester. The
resulting 96:4 mixture of enoate 24 and its E isomer was
carried forward. One-flask acetonide hydrolysis–glycol
cleavage21 exposed the aldehyde function. Condensa-
tion22 with the appropriate keto phosphonate,13 reduc-
tion of the resulting enone with ())-Ipc2BCl23 and
subsequent transesterification24 afforded alcohol 25.
Conversion of 25 to AL-12182 entailed desilylation and
a final chromatography to remove minor congeners.
8. Corey, E. J.; Frederick, J. U.K. Patent Appl. GB
1,539,364 A, 1979.
9. Lourens, G. J.; Koekemoer, J. M. U.S. Patent 4,133,817,
1979.
10. Griffin, B. W.; Williams, G. W.; Crider, J. Y.; Sharif,
N. A. J. Pharmacol. Exp. Ther. 1997, 281, 845.
11. Sharif, N. A.; Xu, S. X.; Williams, G. W.; Crider, J. Y.;
Griffin, B. W.; Davis, T. L. J. Pharmacol. Exp. Ther. 1998,
286, 1094.
12. Klimko, P. G.; Davis, T. L.; Griffin, B. W.; Sharif,
N. A. J. Med. Chem. 2000, 43, 3400, see footnote 18
therein.
13. Bowler, J.; Brown, E. D.; Crossley, N. S.; Heaton, D. W.;
Lilley, T. J.; Rose, N. Prostaglandins 1979, 17, 789.
For larger-scale synthesis we proceeded via aldehyde
26. Condensation25 of 26 (200 g) with Ph3
P@CH(CH2)2CO2-i-Pr afforded ester 27. The derived
aldehyde was subjected to an acid-accelerated Wittig
reaction,26;27 and the resulting enone was reduced with
())-Ipc2BCl at low temperature28 to give 25.29 The
configuration of the new carbinyl stereocenter in 25 was
verified by O-methylmandelic ester analysis.30;31 Pinene-
derived byproducts were conveniently removed after
desilylation of 25 to AL-12182 (Scheme 1).
ꢀ
14. Green, K. Prostaglandins 1978, 15, 813.
15. Klimko, P. G.; Zinke, P. W. U.S. Patent 6,235,779, 2001.
16. Acid 13 was inactive at concentrations up to 100 lM in
stimulating functional activity at the DP, EP2, and EP3
receptors, and exhibited the following PG receptor bind-
ing affinities (Ki, nM): DP, 26,000; EP1, 32,000; EP3, 2000;
EP4, 34,000; IP, >62,000; TP, 25,000.
17. Delgado, P.; Conrow, R. E.; Dean, W. D.; Gaines, M. S.
U.S. Patents 6,441,196, 2002; 6,620,947, 2003.
18. Bock, K.; Pedersen, C.; Thøgersen, H. Acta Chem. Scand.
B 1981, 35, 441.
19. Duclos, A.; Fayet, C.; Gelas, J. Synthesis 1994, 1087.
20. See: Casy, G.; Patterson, J. W.; Taylor, R. J. In Organic
Syntheses; Wiley: New York, 1993; Coll. Vol. VIII, pp
415–420.
21. Xie, M.; Berges, D. A.; Robins, M. J. J. Org. Chem. 1996,
61, 5178.
22. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
23. Itsuno, S. In Organic Reactions; Wiley: New York, 1998;
Vol. 52, pp 430–434.
In conclusion, replacement of the hydroxymethylene
(CHOH) group at the 11-position of the PG cyclopen-
tane nucleus with an oxygen atom maintained potent
(<100 nM) FP receptor-linked biological activity in
many cases. AL-12182, the isopropyl ester prodrug of
the D4 chlorophenoxy acid 13, elicited minimal hyper-
emic response in the rabbit and profoundly lowered IOP
in the ocular hypertensive monkey. A synthetic route
24. Imwinkelried, R.; Schiess, M.; Seebach, D. In Organic
Syntheses; Wiley: New York, 1993; Coll. Vol. VIII, pp
201–204.
beginning with D-sorbitol was employed to prepare
>60 g of AL-12182.
25. Gras, J.-L.; Soto, T.; Viala, J. Tetrahedron: Asymmetry
1999, 10, 139.
References and notes
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1. Clark, A. F. Emerg. Drugs 1999, 4, 333.
2. Alm, A. Curr. Opin. Ophthalmol. 1993, 4, 44.
3. Bito, L. Z. Surv. Ophthalmol. 1997, 41(Suppl. 2), S1.
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