Design and synthesis of 13,14-dihydro prostaglandin F(1α) analogues as potent and selective ligands for the human FP receptor

Article abstract of DOI:10.1021/jm990542v

The in vitro evaluation of a new class of potential bone anabolic agents for the treatment of osteoporosis is described. These compounds are potent and selective ligands for the human prostaglandin F receptor (hFP receptor). The compounds lack the olefin unsaturation required for potency in the natural ligand PGF(2α) yet retain binding affinity for the hFP receptor in the nanomolar to micromolar range. Removal of the alkenes also results in a better selectivity ratio for the hFP receptor over the other prostaglandin receptors tested. A rationale for the selectivity differences of various analogues, based on ligand docking experiments to a putative hFP receptor model, is also described.

Full text of DOI:10.1021/jm990542v

J . Med. Chem. 2000, 43, 945-952
945
Design a n d Syn th esis of 13,14-Dih yd r o P r osta gla n d in F 1r An a logu es a s P oten t
a n d Selective Liga n d s for th e Hu m a n F P Recep tor
Yili Wang, J ohn A. Wos,* Michelle J . Dirr, David L. Soper, Mitchell A. deLong, Glen E. Mieling, Biswanath De,
J ack S. Amburgey, Eric G. Suchanek, and Cynthia J . Taylor
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040
Received October 29, 1999
The in vitro evaluation of a new class of potential bone anabolic agents for the treatment of
osteoporosis is described. These compounds are potent and selective ligands for the human
prostaglandin F receptor (hFP receptor). The compounds lack the olefin unsaturation required
for potency in the natural ligand PGF2R yet retain binding affinity for the hFP receptor in the
nanomolar to micromolar range. Removal of the alkenes also results in a better selectivity
ratio for the hFP receptor over the other prostaglandin receptors tested. A rationale for the
selectivity differences of various analogues, based on ligand docking experiments to a putative
hFP receptor model, is also described.
Sch em e 1
In tr od u ction
It is known within the prostaglandin family that
members of the PGE class and PGF2R produce a bone
anabolic response in several animal models.1 There
remains, however, considerable speculation as to the
exact pathway(s) and receptors responsible for the
anabolic response seen in various models. Naturally
occurring prostaglandins are characterized by their
activity against a particular prostaglandin receptor (i.e.
for PGF2R, the primary mediator of its activity is the
prostanoid receptor type F, the FP receptor, following
the standard nomenclature)2 but generally are not
specific for any one receptor.3 In addition, species-to-
species variations within receptor subtypes can greatly
affect the binding affinity of specific ligands.4
identifying various prostaglandins as potential bone
anabolic agents for the treatment of osteoporosis, we
now wish to disclose the synthesis of and structure-
activity relationship for a novel series of PGF-type
ligands which show a high degree of potency and
specificity for the hFP receptor and, thus, may possess
an enhanced efficacy and a more manageable side effect
profile relative to current prostaglandin treatments
being evaluated.
Ch em istr y
The initial features of the prostaglandin skeleton
which were examined for contribution to the binding
activity of these molecules were the alkenes at positions
C5-C6 and C13-C14. A series of known hFP receptor
ligands were thus converted to their corresponding
saturated counterparts. The synthesis of the saturated
PGF analogues was completed in one of two ways. For
analogues for which the starting material was com-
mercially available, a three-step sequence using esteri-
fication, followed by hydrogenation and deprotection,
was performed as shown in Scheme 1. The formation of
the methyl ester in step a in Scheme 1 increased the
solubility of the prostaglandin, which allowed for the
use of ethyl acetate as solvent in the hydrogenation step.
The use of ethyl acetate resulted in a much cleaner
reduction than hydrogenation of the parent prostaglan-
din in polar, protic solvents (MeOH, EtOH), resulting
in a more efficient process overall. A simple saponifica-
tion completed the synthesis. Compounds 2, 4, 6, and
14 were synthesized in this manner.
Recently, the cloning and expression of the various
prostaglandin receptors have greatly clarified the rela-
tionship between prostaglandin structure and function5
and have raised speculation that highly receptor-selec-
tive ligands could be designed which would eliminate
the deleterious side effects associated with indiscrimi-
nate binding to multiple receptors. As an example,
PGF2R and selective analogues thereof have been stud-
ied for inducing and synchronizing estrus in the field
of animal husbandry6 and for glaucoma management.7
However, little data is available on the specific binding
affinity for these and similar ligands to individual
human receptors, raising questions as to the receptor-
(s) responsible for the pharmacological effects resulting
from these compounds. In addition, it remains unclear
as to which characteristics of these ligands are essential
for binding and efficacy. In the course of our work in
For compounds incorporating a sulfur or nitrogen
atom at the 17-position, the synthetic sequence outlined
* To whom all correspondence should be addressed. Tel: 513-622-
3638. Fax: 513-622-2675. E-mail: wos.ja@pg.com.
10.1021/jm990542v CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

946 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Wang et al.
Sch em e 2
in Scheme 2 was utilized. The commercially available
methyl 7-[3(R)-hydroxy-5-oxo-1-cyclopenten-1-yl]hep-
tanoate (7)8 was silylated using standard conditions9
and then was treated with the cuprate reagent derived
from 4-bromo-1-butene10 to provide the alkene 8. The
stereoselective reduction of the C9 carbonyl (prostag-
landin numbering) proceeded to provide the C9 R-alcohol
as the major isomer (4:1 R/â), which was easily purified
away from the â-isomer using conventional flash silica
gel chromatography. The alcohol was subjected to ep-
oxidation using m-chloroperbenzoic acid, which provided
the epoxide intermediate 9 as an inseparable mixture
of diastereomers at C15.
A regiospecific ring-opening of the epoxide either with
aromatic thiols using triethylamine or with anilines
using magnesium perchlorate provided, after desilyla-
tion, the triol intermediate 10.11 Final deprotection with
aqueous lithium hydroxide provided the carboxylic acid
product 11. The product in all cases proved difficult to
separate by conventional silica gel chromatography
(either normal or reverse phase)12 and was subsequently
tested as the isomeric mixture. Compounds 12, 13, and
15-20 were assembled in this fashion.
by removal of the C5-C6 and C13-C14 olefins. It should
be noted that Cloprostenol (3) appeared to be more
selective for the hFP receptor than PGF2R (1), suggesting
that the aromatic ring may also play a role in enhancing
receptor selectivity. These ideas were subsequently
incorporated into further analogue design.
We subsequently concentrated our effort on generat-
ing additional SAR for 13,14-dihydro PGF1R analogues
which possessed aromatic substituents in the C17-C20
region of the prostaglandin skeleton. We initially syn-
thesized a series of 13,14-dihydro PGF1R analogues with
various heteroaromatic linkages at the C17 position in
order to explore the effect of different heteroatoms at
this position on binding affinity and selectivity. The
results are shown in Table 2.
The results of this SAR study suggest that the
substitution at the C17 position plays an important role
in the in vitro profile of these compounds. For example,
the 17-S linkage proved to be the most potent in the
series, based on the compound 12, with a binding
affinity at the hFP receptor of approximately 2.5 nM
and a good selectivity profile for hFP relative to the
other receptors tested (hEP1/hFP > 100/1). In addition,
although the 17-O compound 6 appears approximately
5× more potent than the 17-N compound 13 (10 nM vs
50 nM at hFP), the latter compound appears to be more
selective for the hFP receptor with a hEP1/hFP ratio of
100, versus approximately 70 for compound 6. The 17-C
linked analogue 14 possessed the poorest affinity for the
hFP receptor (570 nM), with only modest receptor
selectivity (hEP2/hFP ∼ 4.3). Overall, the data suggest
that the sulfur linkage offers the best combination of
receptor potency and selectivity.
Biologica l Resu lts a n d Discu ssion
Initially, PGF2R (1) and Cloprostenol (3) were chosen
in order to study the effects of saturation on the SAR of
the PGF backbone. The results of introducing saturation
are shown in Table 1. While the effect of removing the
C5-C6 and C13-C14 olefins in PGF2R was a 70× decrease
in binding affinity for the hFP receptor (1 vs 2), the
saturated version of Cloprostenol (4) maintained an
equivalent binding affinity of approximately 2 nM for
the hFP receptor when compared to the parent com-
pound (3). In addition, the binding affinity for the other
prostaglandin receptors tested (hEP1, hEP2, hEP3)
decreased with removal of the olefins (4 vs 3), suggesting
that selectivity for the hFP receptor could be increased
We subsequently explored the effect of various meta-
substituents on the sulfur ring in a direct comparison
to compound 4. The results are shown in Table 3. The
results of this study suggest that both a steric and an
electronic requirement appear necessary in order to

13,14-Dihydro PGF1R Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 947
Ta ble 1. Comparison of hFP Binding Data for PGF2R, Cloprostenol, and Saturated Analogues
a
See Experimental Section for details of the receptor binding assay.
achieve optimal potency and selectivity. The unsubsti-
tuted thiophenol 12 and the thiophene 19 were the most
potent compounds tested at 2-6.5 nM. The electron-
deficient m-fluoro- and m-chloro-substituted thiophenols
17 and 18 are approximately 3× less potent than either
unsubstituted aromatic ring; however, they are ap-
proximately 9× more potent than the tolyl analogue 15.
Also of note is the marked lack of binding affinity for
the more polar thiazole 20 in which a nitrogen has been
introduced into the thiophene ring. In general, aromatic
rings with electron-withdrawing substituents appear to
provide enhanced receptor binding affinity relative to
electron-donating substituents.
We have attempted to understand the differences in
the binding affinity of analogues based on a hFP
receptor homology model constructed from the known
human FP receptor amino acid sequencing data13 and
site-directed mutagenesis studies.14 The computer model
F igu r e 1. Receptor model with docked ligand 12.
was created by mapping the transmembrane sections
of the human FP receptor from the primary amino acid
sequence onto the rhodopsin template of the seven-
transmembrane domain receptors available from the
Swiss Institute.15 Individual ligands were then mini-
mized within the putative docking site of the receptor.
As shown in Figure 1, the docking of compound 12 into
the putative receptor site indicates that the extended
top, or R, chain lies in a narrow hydrophobic cleft formed
by Arg-291, Thr-294, Trp-295, and Ile-298 of transmem-
brane (TM) helix 7 and Met-115 of TM3. At one end of
the cleft, a favorable salt bridge forms between the C1
carboxylate of the ligand and the guanidinium group
in Arg-291. It is hypothesized that the methyl group on
Thr-294 creates a steric perturbation in the cleft and
influences the conformation of the R chain. This pre-
ferred conformation orients the cyclopentyl ring of FP-

948 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Wang et al.
Ta ble 2. SAR of Unsubstituted 17-Aryl-13,14-dihydro PGF1R Analogues
a
b
See Experimental Section for details of the receptor binding assay. Tested as a 1:1 mixture of diastereomers at C15 (prostaglandin
numbering).
type ligands so the C9 sp3 hydroxyl can favorably
hydrogen bond with the hydroxyl on Thr-294 while the
C11 hydroxyl can form a hydrogen bond with Ser-258.
The receptor site model also suggests that the ω chain
(C17-C20 region) lies in an adjacent hydrophobic pocket
formed by residues Leu-204, Phe-205, and Leu-208 of
TM5, Cys-259 and Leu-266 of TM6, and Met-115 of
TM3. Hydrophobic interactions position the C15 hydroxyl
within hydrogen-bonding distance of Ser-263 on TM6.
The low binding of saturated aliphatic compounds is
perhaps rationalized by an increase in the number of
degrees of freedom allowed to assume unproductive
conformers. Within the aromatic series, it is plausible
that the increased binding affinity of compounds such
as 4, 12, and 19 may be the result of conformational
compensation from the aryl “tail” of the ligand via a
favorable π-stacking interaction with aromatic amino
acid residues (i.e. Phe-205) at the receptor surface.16
This phenomenon may also enhance receptor selectivity,
in addition to selectivity derived from the area occupied
by the aromatic substitutions near Val-164 on TM4 and
Val-116 on TM3 in the hFP receptor.
C17-C20 region, e.g., 16-phenoxy-16-tetranor analogue
6, maintain nanomolar binding affinity and selectivity
for the hFP receptor. However, saturated derivatives
of PGF-type prostaglandins which contain the acyclic
C17-C20 ω chain, e.g., PGF2R, were found to possess
weak binding affinity for the receptor. On the basis of
these initial observations, we have designed a series of
novel saturated PGF analogues which possess good
binding affinity and selectivity for the human FP
receptor. In addition, preliminary results of these
compounds in vivo demonstrate that they are bone
anabolic agents in the OVX rat model.17 It should be
noted that the ability to design receptor-selective pros-
taglandin analogues has potential application in a
number of areas where prostanoids are currently being
developed for and/or used as therapeutic agents.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded on a
Varian Unity Plus 300 MHz spectrometer and are referenced
to either the deuteriochloroform singlet at 7.27 ppm or
deuteriomethanol singlet at 4.87 ppm. 13C NMR spectra were
obtained on a Varian Unity Plus 300 MHz spectrometer and
are referenced at either the center line of the deuteriochloro-
form triplet at 77.0 ppm or the deuteriomethanol heptet at
49.15 ppm. Infrared absorption spectra were obtained on a
Perkin-Elmer model 197 spectrophotometer and are referenced
to polystyrene (1601 cm-1). Mass spectra were obtained on
either a Fison Platform-II Quadrupole mass spectrometer or
a Fison Trio2000 Quadrupole mass spectrometer. High-resolu-
tion mass spectra were obtained from the Procter & Gamble
Con clu sion
The results from these studies demonstrate that
unsaturation of the top and bottom chains in the PGF
series is not necessarily critical for maintaining binding
affinity for the hFP receptor. The 13,14-dihydro PGF1R
derivatives which contain aromatic substitution at the

13,14-Dihydro PGF1R Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 949
Ta ble 3. SAR of Various 3-Substituted-17-phenylthio-13,14-dihydro PGF1R Analogues
a
b
See Experimental Section for details of the receptor binding assay. Tested as a 1:1 mixture of diastereomers at C15 (prostaglandin
numbering).
CRD Mass Spectrometry Lab (M. Lacey). Elemental analyses
were obtained from the Procter & Gamble EA Lab in Norwich,
NY. Melting points were determined in open Pyrex capillary
tubes on a Thomas-Hover Unimelt apparatus. Melting points
and boiling points are uncorrected. All solvents were purchased
anhydrous (Aldrich Chemical) and used without further
purification. PGF2R, 13,14-dihydro PGF1R, Cloprostenol, 16-
phenoxy PGF2R, and 17-phenyl PGF2R were purchased from
Cayman Chemical and used without further purification.
Methyl 7-[3(R)-hydroxy-5-oxo-1-cyclopenten-1-yl]heptanoate
was purchased from Sumitomo Chemical and used without
purification. All air-sensitive reactions were performed under
an anhydrous nitrogen atmosphere. Flash chromatography
was performed on silica gel (70-230 mesh, Aldrich; or 230-
400 mesh, Merck) as appropriate. Thin-layer chromatography
analysis was performed on glass mounted silica gel plates
(200-300 mesh; Baker) and visualized using UV, 5% phos-
phomolybdic acid in EtOH, or ammonium molybdate/cerric
sulfate in 10% aqueous H2SO4.
CaCl2, MgCl2, MgSO4, or phenol red). The cells were detached
with versene, and HBSS was added. The mixture was centri-
fuged at 200g for 10 min, at 4 °C to pellet the cells. The pellet
was resuspended in phosphate-buffered saline-EDTA buffer
(PBS, 1 mM EDTA, pH 7.4, 4 °C). The cells were disrupted by
nitrogen cavitation (Parr model 4639), at 800 psi, for 15 min
at 4 °C. The mixture was centrifuged at 1000g for 10 min at
4 °C. The supernatant was centrifuged at 100000g for 60 min
at 4 °C. The pellet was resuspended to 1 mg protein/mL TME
buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA, pH 6.0, 4 °C)
based on protein levels measured using the Pierce BCA protein
assay kit. The homogenate was mixed using a Kinematica
polytron for 10 s. The membrane preparations were then
stored at -80 °C, until thawed for assay use.
The receptor competition binding assays were developed in
a 96-well format. Each well contained 100 µg of hFP mem-
brane, 5 nM [3H]PGF2R, and the various competing compounds
in a total volume of 200 µL. The plates were incubated at 23
°C for 1 h. The incubation was terminated by rapid filtration
using the Packard Filtermate 196 harvester through Packard
UniFilter GF/B filters that were prewetted with TME buffer.
The filter was washed four times with TME buffer. Packard
Microscint 20, a high-efficiency liquid scintillation cocktail, was
Ra d ioliga n d Bin d in g Assa y. COS-7 cells were transiently
transfected with a hFP recombinant plasmid using Lipo-
fectAMINE reagent. 48 h later, the transfected cells were
washed with Hank’s balanced salt solution (HBSS, without

950 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Wang et al.
added to the filter plate wells and the plates remained at room
temperature for 3 h prior to counting. The plates were read
on the Packard TopCount microplate scintillation counter.
2.52 (dd, J ) 5.0, 11.1 Hz, 1H), 2.24 (t, J ) 7.5 Hz, 2H), 2.15-
1.10 (m, 17H), 0.83 (s, 9H), 0.03 (d, J ) 8.7 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 202.1, 174.5, 138.5, 115.1, 73.7, 53.5, 51.7,
48.9, 47.8, 34.3, 31.9, 29.6, 27.1, 25.9, 25.1, 18.1, -4.3, -4.6;
MS m/z 410 (M + NH4)+ 428.5. Anal. (C23H42O4Si) C, H.
The hEP1 receptor was transiently expressed in COS-7 cells
and followed the above-mentioned transient transfection pro-
tocol. Five of the other receptors, hEP2, hEP3, hEP4, hTP, and
hIP, were stably expressed in the CHO cell line. The hDP
receptor was stably expressed in the HEK-293 cell line and
required a TME buffer pH of 7.4. The CHO cells, and HEK-
293 cells expressing the receptors were collected 4-5 days after
seeding, washed with PBS, and detached with versene. Cells
were centrifuged at 100g for 10 min at 4 °C. Cells were
resuspended in lysis buffer (10 mM Tris-HCl, 5 mM EDTA,
10 µg/mL leupeptin and benzamidine, 2 µg/mL aprotinin) and
the homogenate was centrifuged at 200g for 10 min at 4 °C.
The supernatant was centrifuged at 100000g for 60 min at 4
°C. The pellet was resuspended to 1 mg protein/mL TME buffer
based on measured protein levels. The homogenate was mixed
using a Kinematica polytron for 10 s. The membrane prepara-
tions were then stored at -80 °C, until thawed for assay use.
The radiolabeled ligands used for the competition binding
assays of the other seven receptors were as follows: the EP1,
EP2, EP3, and EP4 assays used [3H]PGE2, the DP assay used
[3H]PGD2, the IP assay used [3H]Iloprost, and the TP assay
used [3H]SQ-29548. All of the radiolabeled ligands were run
at 5 nM in the experiment and were purchased from DuPont
NEN and Amersham Life Science.
Meth yl 7-(2-Hyd r oxy-5-(2-(2-oxir a n yl)eth yl)-4-(1,1,2,2-
tetr a m eth yl-1-sila p r op oxy)cyclop en tyl)h ep ta n oa te (9).
The ketone 8 (11.0 g, 26.8 mmol, 1 equiv) was dissolved in
MeOH (30 mL) and cooled to -40 °C. Sodium borohydride (912
mg, 24.12 mmol, 0.9 equiv) was added portionwise over 10 min.
After the addition was completed, the reaction was stirred for
13 h at -40 °C and then 12 h at -78 °C. The reaction was
quenched with water, partitioned between brine and CH2Cl2
and the layers separated. The aqueous layer was back-
extracted with CH2Cl2 (3 × 200 mL) and the organic layers
combined and dried (Na2SO4). The solvent was removed in
vacuo and the residue chromatographed on silica gel (30%
EtOAc/hexanes) to give 8.2 g (61%) of the alcohol as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 5.80 (dq, J ) 6.0, 16.6 Hz,
1H), 4.94 (overlapping dd, J ) 1.8, 11.4 Hz and 3.3, 11.4 Hz,
2H), 4.09 (m 1H), 4.00 (d, J ) 4.5 Hz, 1H), 3.60 (s, 3H), 2.95
(br s, OH, 1H), 2.30 (t, J ) 7.5 Hz, 1H), 2.10-1.05 (m, 18 H),
0.85 (s, 9H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 174.5,
138.7, 114.8, 80.1, 75.4, 53.4, 52.2, 51.6, 42.4, 34.4, 34.2, 32.5,
30.4, 29.9, 29.4, 28.6, 25.9, 25.2, 17.9, -4.5; MS m/z 412 (M +
H)+ 413.4. Anal. (C23H44O4Si) C, H.
The alcohol (4.05 g, 9.83 mmol, 1 equiv) was dissolved in
CH2Cl2 (100 mL) and cooled to 0 °C. Sodium bicarbonate (100
mg) was added, followed by m-CPBA (57-85% purity) (5.10
g, 29.5 mmol, 3 equiv) portionwise over 15 min. After the
addition was completed, the reaction was stirred for 20 h at
rt. The reaction was poured onto water, partitioned between
brine and CH2Cl2 and the layers separated. The aqueous layer
was back-extracted with CH2Cl2 (3 × 200 mL) and the organic
layers combined, washed with satd Na2S2O3 (4 × 250 mL), satd
NaHCO3 (3 × 250 mL) and dried (Na2SO4). The solvent was
removed in vacuo and the resulting oil can be used crude or
can be purified by chromatography on silica gel (20% EtOAc/
hexanes) to provide 3.0 g (73%) of the epoxide diastereomers
9 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 4.09 (t, J )
4.8 Hz, 1H), 3.96 (d, J ) 4.2 Hz, 1H), 3.65 (s, 2H), 2.90 (m,
1H), 2.75 (m, 1H), 2.48 (m, 1H), 2.30 (t, J ) 7.5 Hz, 2H), 1.90-
1.29 (m, 20 H), 0.80 (s, 9H), 0.03 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 174.5, 80.0, 79.9, 75.2, 52.1, 52.0, 51.6, 47.3, 47.2,
42.4, 34.3, 31.3, 31.2, 30.8, 30.4, 30.3, 29.8, 28.5, 25.9, 17.9,
-4.5; MS m/z 428 (M + H)+ 429.4. Anal. (C23H44O5Si) C, H.
Gen er a l P r oced u r e for Syn th esis of 13,14-Dih yd r o-16-
p h en ylth io-16-tetr a n or P GF 1R Meth yl Ester s. In a 5 mL
round-bottom flask, 0.2 g of epoxide 9 (0.47 mmol) and dry
benzene (100 uL) were added. The flask was cooled at 0 °C,
then treated with the appropriate thiol (0.56 mmol, 1.2 equiv)
and triethylamine (0.56 mmol, 1.2 equiv). The ice bath was
removed and the reaction was stirred at room temperature
under nitrogen for 20 h. An excess amount of thiophenol was
added as necessary. The reaction was quenched with brine,
and extracted with CH2Cl2 (3 × 10 mL). The organic layer was
washed three times with 1 N HCl, brine, dried (Na2SO4), and
concentrated. Without further purification to this crude reac-
tion mixture, 3 mL of CH3CN and 0.5 mL of HF/pyridine were
added while the flask was kept at 0 °C. After 3 h at 0 °C, the
reaction was quenched with satd NaCl. The aqueous layer was
extracted three times with CH2Cl2. The organic layers were
combined and washed three time with 1 N HCl, brine, and
dried (Na2SO4) to provide the crude product. Silica gel chro-
matography purification (7:3 hexanes/ethyl acetate) provided
pure thiol methyl ester.
Meth yl 7-(5-Bu t-3-en yl-2-h ydr oxy-4-(1,1,2,2-tetr am eth yl-
1-sila p r op oxy)cyclop en tyl)h ep ta n oa te (8). To a solution
of methyl 7-[3(R)-hydroxy-5-oxo-1-cyclopenten-1-yl]heptanoate
(7) (10.0 g, 41.66 mmol, 1 equiv) in CH2Cl2 (200 mL) at -78
°C was added 2,6-lutidine (6.31 mL, 54.16 mmol, 1.3 equiv)
dropwise over 15 min. The solution was kept at -78 °C, and
TBDMS triflate (11.46 mL, 49.92 mmol, 1.2 equiv) in CH2Cl2
(50 mL) was added dropwise over 15 min. The reaction was
warmed gradually to rt and stirred at rt for 15 h. Aqueous
10% HCl was added and the layers were separated. The water
layer was extracted with 200 mL CH2Cl2 and the organic layers
were combined. The organic layer was washed with brine,
dried (Na2SO4) and concentrated. The residue was distilled
under vacuum (house vacuum, 10 mmHg) to provide 13.3 g
(89%) of the silyl ether as a yellow liquid: bp 175-180 °C; 1H
NMR (300 MHz, CDCl3) δ 6.94 (br s, 1H), 4.85 (m, 1H), 3.65
(s, 3H), 2.65 (dd, J ) 6.0, 18.0 Hz, 1H), 2.10-1.95 (m, 5H),
1.65-1.10 (m, 8H), 0.83 (s, 9H), 0.04 (d, J ) 3.3 Hz, 6 H); 13
C
NMR (75 MHz, CDCl3) δ 206.1, 174.4, 158.6, 147.3, 69.2, 51.6,
45.7, 45.1, 34.2, 29.2, 29.0, 27.4, 26.0, 25.6, 25.0, 24.6, 18.3,
-3.4, -4.5; MS m/z 354 (M + H)+ 355.2, (M + NH4)+ 372.2;
HRMS calcd for (C19H34O4Si + H)+ 355.2305, found 355.2304.
To a slurry of Mg0 powder (1.34 g, 55.86 mmol, 2 equiv) in
THF (75 mL) at rt were added one crystal I2 and 4-bromo-1-
butene (5.67 mL, 55.86 mmol, 2 equiv) dropwise over 10 min.
The reaction proceeded to exotherm as the addition continued.
After the addition was complete, the reaction was refluxed for
3 h and cooled to rt. The Grignard was diluted with 50 mL
THF and added via cannula to a three-necked flask, equipped
with mechanical stirring, and charged with CuBr‚DMS (11.48
g, 55.86 mmol, 2 equiv) in 100 mL of a 1:1 solution of THF/
DMS at -78 °C. After the addition of the Grignard (∼20 min),
the reaction was stirred 1 h at -78 °C. The color of the reaction
was dark red at this point. A solution of the silyl ether (10.0
g, 27.93 mmol, 1 equiv) in THF (25 mL) was then added
dropwise over 25 min. The reaction was stirred at -78 °C for
15 min, then allowed to warm slowly to rt over 2 h. The
reaction was quenched with aq NH4Cl and the excess DMS
allowed to evaporate overnight. The reaction was partitioned
between brine/CH2Cl2 and the layers separated. The aqueous
layer was back-extracted with 3 × 200 mL CH2Cl2 and the
organic layers were combined and dried (Na2SO4). The solvent
was removed in vacuo and the residue chromatographed on
silica gel (10% hexane/EtOAc) to give 8.13 g (71%) of the ketone
8 as a clear oil: 1H NMR (300 MHz, CDCl3) δ 5.76 (dq, J )
6.0, 16.6 Hz, 1H), 4.94 (overlapping dd, J ) 1.8, 11.4 Hz and
3.3, 11.4 Hz, 2H), 4.01 (dd, J ) 5.7, 6.0 Hz, 1H), 3.61 (s, 3H),
Gen er a l P r oced u r e for Syn th esis of 13,14-Dih yd r o-16-
p h en yla m in o-16-tetr a n or P GF 1R Meth yl Ester s To a 10
mL round-bottom flask were added THF (2 mL), 0.36 g of
epoxide 9 (1.26 mmol), aniline (1.26 mmol, 1.5 equiv), and 10
mg of magnesium perchlorate. The reaction was refluxed under
nitrogen for 3 h, cooled to room temperature, and the solvent
removed in vacuo. Without further purification to the crude
reaction mixture, 3 mL of CH3CN and 0.5 mL of HF/pyridine

13,14-Dihydro PGF1R Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 951
were added while the flask was kept at 0 °C. After 5 h at 0 °C,
the reaction was quenched with satd NaCl. The aqueous layer
was extracted three times with CH2Cl2. The organic layers
were combined and washed three time with satd NaHCO3,
brine, dried (Na2SO4), and the resulting oil purified by silica
gel chromatography (95% CH2Cl2, 5% MeOH) to provide 0.182
g (35%) of the methyl ester of 13 as a clear oil: 1H NMR (300
MHz, CDCl3) δ 1.32-1.75 (m, 20H), 1.87 (br s, 2H), 2.27-2.33
(t, J ) 7.5 Hz, 2H), 2.27 (s, 3H), 2.97-3.04 (m, 1H), 3.19-3.24
(dd, J ) 2.7, 13.6 Hz, 1H), 3.66 (s, 3H), 3.84 (s, 1H), 3.91 (s,
1H), 4.167 (s, 1H), 6.45-6.47 (m, 2H), 6.54-6.56 (dd, J ) 7.5
Hz, 1H), 7-7.08 (dd, J ) 7.8, 8.4 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 21.8, 25.0, 28.3, 28.8, 28.9, 29.2, 29.7, 30.0, 33.2,
33.764, 34.2, 42.4, 42.5, 50.5, 51.7, 51.8, 52.2, 52.9, 70.5, 70.6,
74.3, 74.4, 78.2, 78.7, 110.7, 114.3, 118.9, 129.3, 139.1, 148.5,
174.7; MS m/z 408 (M + H)+ 408.3.
Gen er a l P r oced u r e for Sa p on ifica tion of Meth yl Ester
to F r ee Acid . To a 5 mL round-bottom flask was added the
appropriate PGF1R methyl ester (0.012 mmol.). A mixture of
THF/water solution (4 mL; 3:1 THF:H2O) was added, and the
flask was cooled to 0 °C. An excess amount of lithium
hydroxide (2.5 equiv) was added, the ice bath was removed,
and the reaction stirred at room temperature overnight. The
reaction was diluted with CH2Cl2 and satd citric acid and the
layers separated. The aqueous layer was washed with CH2-
Cl2 (3 × 10 mL) and the organic layers were combined and
washed with brine, dried (Na2SO4) and concentrated. Column
chromatography on silica gel (CH2Cl2/CH3OH/AcOH, 9.6/0.3/
0.1) provided the desired free acid.
127.8, 133.3, 176.4; MS m/z 411 (M + H)+ 411.4; HRMS calcd
for (C22H34O5S + H)+ 411.2205, found 411.2197.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-(3-m eth ylp h en ylth io)-
bu tyl)cyclop en tyl)h ep ta n oic a cid (15): 49% yield; IR (neat)
3391, 2927, 2855, 1709, 1592, 1415, 1217, 1079, 774, 689 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.25-1.74 (m, 19H), 1.86 (br s,
2H), 2.29-2.37 (m, 5H), 2.86-2.93 (dd, J ) 8.4, 13.5 Hz, 1H),
3.08-3.14 (dd, J ) 3.7, 13.5 Hz, 1H), 3.68-3.71 (m, 1H), 3.95
(s, 1H), 4.10-4.17 (s, 1H), 5.30-5.31 (br s, 1H), 7.00-7.03 (dd,
J ) 7.5, 3.3 Hz, 1H), 7.17 (m, 3H); 13C NMR (75 MHz, CDCl3)
δ 21.5, 24.7, 28.0, 28.8, 28.9, 29.5, 29.6, 34.4, 41.9, 42.1, 42.5,
42.6, 51.6, 51.7, 52.6, 52.8, 69.8, 70.2, 74.4, 78.4, 78.8, 127.1,
127.6, 129.1, 130.7, 135.3, 139.1, 178.6; MS m/z 425 (M + H)+
425.4; HRMS calcd for (C23H36O5S + H)+ 425.2331, found
425.2336. Anal. (C23H36O5S‚1H2O) C, H.
7-(5-(4-(3-F lu or op h en ylth io)-3-h yd r oxybu tyl)-2,4-d ih y-
d r oxycyclop en tyl)h ep ta n oic a cid (18): 89% yield; IR (neat)
3369, 2928, 2855, 1708, 1599, 1578, 1474, 1427, 1264, 1215,
1
1066, 881, 775, 730, 678 cm-1; H NMR (300 MHz, CDCl3) δ
1.20-1.79 (m, 19H), 1.88 (br s, 2H), 2.31-2.36 (t, J ) 7.2 Hz,
2H), 2.93-3.00 (dd, J ) 7.8, 13.5 Hz, 1H), 3.11-3.15 (m, 1H),
3.76-3.77 (m, 1H), 3.97 (s, 1H), 4.19 (s, 1H), 5.21 (br s, 1H),
6.85-6.92 (dd, J ) 2.4, 8.4 Hz, 1H), 7.05-7.14 (m, 2H), 7.18-
7.30 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 24.6, 27.9, 28.8,
29.3, 29.7, 30.5, 34.0, 34.6, 41.7, 41.9, 42.6, 42.8, 51.7, 51.9,
53.0, 53.2, 69.7, 70.2, 74.7, 78.7, 78.8, 113.4, 113.7, 116.1, 116.4,
125.1, 128.4, 130.5, 130.6, 125.1, 128.4, 130.5, 130.6, 138.2,
138.5, 161.9, 165.4, 178.3; 19F NMR (CDCl3) δ 54.87, 54.85,
54.87, 54.90, 54.93; MS m/z 429 (M + H)+ 429.3; HRMS calcd
for (C22H33O5SF + H)+ 429.211, found 429.2096. Anal. (C22H33O5-
SF‚1.5H2O) H; C: calcd, 58.00; found, 58.57.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-(p h en yla m in o)bu tyl)-
cyclop en tyl)h ep ta n oic a cid (13): 57% yield; 1H NMR (300
MHz, CD3OD) δ 7.12 (dd, J ) 7.2, 8.4 Hz, 2H), 6.67 (m, 3H),
4.12 (br s, 1H), 3.89 (q, J ) 3.6, 7.2 Hz, 1H), 3.64 (br s, 1H),
3.20 (dd, J ) 4.5, 12.9 Hz, 1H), 3.05 (dd, J ) 7.5, 12.9 Hz,
1H), 2.31 (t, J ) 7.2 Hz, 2H), 2.10 (m, 1H), 1.77-1.36 (m, 22H);
13C NMR (75.5 MHz, CD3OD) δ 179.0, 150.1, 130.1, 118.3,
114.4, 78.5, 73.8, 71.5, 71.3, 52.7, 52.6, 43.8, 43.7, 35.6, 34.1,
34.0, 30.9, 30.4, 30.1, 29.6, 29.5, 29.1, 26.3; MS m/z 393 (M +
H)+ 394.3; HRMS calcd for (C22H35O5N + H)+ 394.2593, found
394.2585. Anal. (C22H35O5N‚1H2O) C, N; H: calcd, 9.06; found,
8.32.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-(3-t r iflu or om et h yl-
p h en ylth io)bu tyl)cyclop en tyl)h ep ta n oic a cid (16): 84%
yield; IR (neat) 3369, 2929, 1708, 1421, 1323, 1166, 1125, 1073,
1
696 cm-1; H NMR (300, MHz, CDCl3) δ 1.20-1.95 (m, 21H),
2.29-2.34 (t, J ) 7.2 Hz, 2H), 2.97-3.05 (dd, J ) 7.8, 13.5
Hz, 1H), 3.13-3.19 (dt, J ) 3.3, 13.5 Hz, 1H), 3.76-3.79 (m,
1H), 3.97 (s, 1H), 4.18 (s, 1H), 5.820 (br s, 1H), 7.29-7.43 (m,
2H), 7.51-7.53 (d, J ) 6.9 Hz, 1H), 7.583 (br s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 24.7, 27.8, 28.8, 29.4, 30.0, 34.5, 34.7,-
41.2, 41.4, 42.4, 51.6, 52.3, 52.6,70.0, 70.4, 74.3, 78.3, 78.6,
122.1, 122.9, 125.5, 125.8, 129.5, 130.8, 131.2, 131.7, 132.2 (d,
J ) 128.7 Hz), 138.0, 179.0; 19F NMR (CDCl3) 103.9; MS m/z
448 (M + H)+ 479.3; HRMS calcd for (C23H33O5SF3 + H)+
479.2079, found 479.2076. Anal. (C23H33O5SF3‚0.5H2O) C, H.
7-(5-(4-(3-Ch lor op h en oxy)-3-h yd r oxyb u t yl)-2,4-d ih y-
d r oxycyclop en tyl)h ep ta n oic a cid (4):18 47% yield; IR (thin
film) 3378, 2928, 2859, 1707, 1594, 1479, 1248 cm-1; 1H NMR
(300 MHz, CD3OD) δ 7.28 (m, 1H), 6.95 (m, 3H), 4.12 (br s,
1H), 3.95 (m, 5H), 3.35 (m, 2H), 2.05 (m, 1H), 1.10-1.80 (m,
20H); 13C NMR (CD3OD, 75.5 MHz) δ 24.9, 27.9, 28.2, 28.6,
29.1, 29.7, 31.2, 33.9, 42.8, 50.1, 51.1, 69.8, 72.4, 77.3, 113.0,
114.9, 120.7, 130.4, 134.7, 160.2, 176.6; MS (+ES) m/z (relative
intensity) 446.1 (M + NH4+, 50), 429.1 (M + H+, 100), 393.1
(M - 2H2O, 25); HRMS (FAB+) calcd for (C22H33O6Cl + Na)+
451.1863, found 451.1880.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-(2,5-t h ia zolylt h io)-
bu tyl)cyclop en tyl)h ep ta n oic a cid (20): 62% yield; IR
(neat) 3368, 2925, 2853, 1710, 1384, 1302, 1026, 912, 730 cm-
;
1
1H NMR (300 MHz, CDCl3) δ 1.35-1.74 (m, 19H), 1.90 (s, 2H),
2.32-2.37 (t, J ) 7.2 Hz, 2H), 3.19-3.27 (ddd, J ) 1.8, 7.2,
14.4 Hz, 1H), 3.35-3.42 (br d, J ) 2.7, 14.4 Hz, 1H), 4.01 (br
s, 2H), 4.20 (s, 1H), 5.21 (br s, 1H), 7.24-7.25 (d, J ) 3.6 Hz,
1H), 7.64-7.65 (d, J ) 3.3 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 24.7, 27.9, 28.7, 29.3, 29.8, 30.3, 41.9, 42.0, 42.6, 42.6,
51.7, 51.7, 52.8, 53.0, 71.4, 71.7, 74.6, 78.6, 78.7, 119.8, 142.3,
165.8, 178.3; MS m/z 417 (M + H)+ 418.1; HRMS calcd for
(C19H31O5S2N + H)+ 418.1722, found 418.1726.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-p h en oxybu tyl)cyclo-
p en tyl)h ep ta n oic a cid (6):18 67% yield; 1H NMR (300 MHz,
CD3OD) δ 7.30 (t, J ) 7.5 Hz, 2H), 6.95 (br d, J ) 8.1 Hz, 3H),
4.15 (br s, 1H), 3.95 (m, 5H), 3.35 (m, 2H), 2.10 (t, J ) 7.0 Hz,
2H), 1.15-1.90 (m, 19 H); MS ESI m/e 395 (M+).
7-(5-(4-(3-Ch lor op h en ylth io)-3-h yd r oxybu tyl)-2,4-d ih y-
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-5-p h en ylp en t yl)cyclo-
p en tyl)h ep ta n oic a cid (14):18 62% yield; 1H NMR (300 MHz,
CD3OD) δ 7.30 (t, J ) 7.5 Hz, 2H), 6.95 (br d, J ) 8.1 Hz, 3H),
4.15 (br s, 1H), 3.95 (m, 5H), 3.35 (m, 2H), 2.10 (t, J ) 7.0 Hz,
2H), 1.15-1.90 (m, 19 H); MS ESI m/e 395 (M+).
d r oxycyclop en tyl)h ep ta n oic a cid (17): 89% yield; IR (neat)
1
3369, 2926, 1707, 1577, 1461, 1072, 777, 678 cm-1; H NMR
(300 Hz, CDCl3) δ 1.20-1.73 (m, 19H), 1.88 (br s, 2H), 2.31-
2.36 (t, J ) 7.2 Hz, 2H), 2.91-2.99 (dd, J ) 13.5, 8.1 Hz,1H),
3.10-3.17 (ddd, J ) 13.5, 3.6, 2.7 Hz, 1H), 3.73-3.76 (m, 1H),
3.97 (s, 1H), 4.19 (s, 1H), 4.68 (br s, 1H), 7.15-7.20 (m, 1H),
7.22-7.27 (m, 2H), 7.35 (br s, 1H); 13C NMR (75.5 Hz, CDCl3)
δ 24.7, 27.9, 28.8, 29.4, 29.6, 30.2, 34.2, 34.5, 41.6, 41.8, 42.6,
51.8, 52.6, 52.9, 69.9, 70.3, 74.5, 78.5, 78.7, 126.7, 127.6, 129.1,
130.3, 135.0, 138.1, 178.6; MS m/z 444 (M + Na)+ 467.0; HRMS
calcd for (C22H33O5SCl + Na)+ 467.1635, found 467.1654. Anal.
(C22H33O5SCl‚0.75H2O) C, H.
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-p h en ylt h iob u t yl)cy-
clop en tyl)h ep ta n oic a cid (12): 63% yield; IR (thin film)
3388, 2927, 2954, 1708, 1583, 1438, 1113, 1024, 739, 691 cm-1
;
1H NMR (300 Hz, CDCl3) δ 1.28-1.75 (m, 19H), 1.86 (br s,
2H), 2.30-2.35 (t, J ) 7.2 Hz, 2H), 2.87-2.95 (dd, J ) 8.4,
13.5 Hz, 1H), 3.10-3.16 (dd, J ) 3.3, 13.5 Hz, 1H), 3.69-3.71
(m, 1H), 3.95 (s, 1H), 4.17 (s, 1H), 5.20 (br s, 1H), 7.18-7.23
(m, 1H), 7.27-7.32 (overlapping dd, J ) 7.2, 7.8 Hz, 2H), 7.37-
7.40 (d, J ) 7.5 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 22.5,
25.7, 26.5, 26.7, 27.2, 27.4, 28.0, 32.2, 39.8, 40.0, 40.3, 40.4,
48.4, 49.5, 50.4, 50.7, 67.6, 67.9, 72.3, 76.2, 76.4, 124.5, 127.1,
7-(2,4-Dih yd r oxy-5-(3-h yd r oxy-4-(2-th ien ylth io)bu tyl)-
cyclop en tyl)h ep ta n oic a cid (19): 75% yield; IR (neat) 3369,
2926, 2851, 1708, 1407, 1213, 1109, 1072, 1022, 985, 840 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.20-1.87 (m, 19H), 1.87 (br s,

952 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Wang et al.
(9) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. Studies with Trialkyl-
silyltriflates: New Syntheses and Applications. Tetrahedron
Lett. 1981, 22, 3455-3548.
2H), 2.31-2.36 (t, J ) 7.2 Hz, 2H), 2.75-2.82 (dd, J ) 13.5,
8.4 Hz, 1H), 2.94-3.00 (ddd, J ) 13.5, 3.6, 1.8 Hz, 1H), 3.71-
3.74 (m, 1H), 3.96 (s, 1H), 4.18 (s, 1H), 4.92 (br s, 1H), 6.97-
7.00 (dd, J ) 5.4, 3.6 Hz, 1H), 7.15-7.17 (dd, J ) 3.6, 1.2 Hz,
1H), 7.35-7.37 (dd, J ) 5.4, 1.2 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 24.7, 28.0, 28.8, 28.9, 29.5, 29.7, 30.2, 34.2, 42.0, 42.7,
46.6, 46.8, 51.6, 51.7, 52.6, 53.0, 69.8, 70.1, 74.5, 78.5, 78.7,
127.9, 129.8, 133.6, 134.2, 178.5; MS m/z 416 (M + H)+ 417.2.
Anal. (C20H32O5S2‚0.5CH3OH) C, H.
(10) (a) House, H. O.; Chu, C. Y.; Wilkins, J . M.; Umen, M. J . The
Chemistry of Carbanions. XXVII. A Convenient Precursor for
the Generation of Lithium Organocuprates. J . Org. Chem. 1975,
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Copper (I) Catalyzed Reactions of Organolithiums and Grignard
Reagents. Tetrahedron 1984, 40, 641-657.
(11) For a review see: Smith, J . G. Synthetically Useful Reactions
of Epoxides. Synthesis 1984, 629-656 and references therein.
(12) The diastereomers can be separated using normal-phase (Chiral-
cel OJ , 4.6 × 100 mm column, 80:20:0.1 hexane/2-propanol/0.1%
acetic acid) or reverse-phase (Inertsil ODS2, 0.1% TFA/H2O in
methanol) chromatography.
Ackn owledgm en t. We thank Greg Bosch and Arthur
Grieb of the Custom Chemistry Scaleup Unit for chro-
matography assistance and Martin Lacey of the Corpo-
rate Research Analytical Group for HRMS data.
(13) (a) Abramovitz, M.; Boie, Y.; Nguyen, T.; Rushmore, T. H.;
Bayne, M. A.; Metters, K. M.; Slipetz, D. M.; Grygorczyk, R.
Cloning and Expression of a cDNA for the Human Prostanoid
FP Receptor. J . Biol. Chem. 1994, 269, 2632-2636. (b) Pierce,
K. L.; Bailey, T. J .; Hoyer, P. B.; Gil. D. W.; Woodward, D. F.;
Regan, J . W. Cloning of a Carboxyl-terminal Isoform of the
Prostanoid FP Receptor. J . Biol. Chem. 1997, 272, 883-887 and
references therein.
(14) (a) Funk, C. D.; Furci, L. Moran, N.; Fitzgerald, G. A. Point
Mutation in the Seventh Hydrophobic Domain of the Human
Thromboxane A2 Receptor Allows Discrimination between Ago-
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934-939. (b) Cascierci, M. A.; Fong, T. M.; Strader, C. D.
Identification of critical functional groups within binding pockets
of G-protein-coupled receptors. Drugs Future 1996, 21, 521-527.
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Automated Modeling of the Transmembrane Region of G-coupled
Protein Receptor by Swiss-model. Receptors Channels 1996, 4,
161-164. (b) Using TRIPOS computational tools (Sybyl 6.6),
several variants of the hFP receptor model were created with
the mapping procedure described in the text. Several orienta-
tions of various receptor helices were investigated, and different
conformations of known FP agonists were docked into the
putative models and evaluated. The homology model presented
in this paper best explains the SAR data discussed.
(16) We have attempted to probe receptor pocket “depth” with para-
substituted analogues of compound 12. In general, these com-
pounds were 3-10-fold less potent at the hFP receptor (i.e. p-F
) 75 nM, p-CH3 ) 744 nM) than the meta-substituted analogues,
suggesting that a finite space exists at the bottom of the receptor.
(17) (a) Hartke, J . R.; Lundy, M. W.; deLong, M. A. Method of
Increasing Bone Volume Using Non-Naturally Occurring FP
Agonists. WO 9912550, 1999; Chem. Abstr. 1999, 194004. (b)
Wos, J . A.; deLong, M. A.; Amburgey, J . S.; De, B.; Dai, G.; Wang,
Y. Aromatic C16-C20-Substituted Tetrahydro Prostaglandins
Useful as FP Agonists. WO 9912895, 1999; Chem. Abstr. 1999,
194115. (c) Wos, J . A.; deLong, M. A.; Amburgey, J . S.; De, B.;
Dai, G.; Wang, Y. A Process for Making 13,14-Dihydro-15,-16,-
17-Substituted16-Tetranor or 17-Trinor Prostaglandin F1R Ana-
logues. WO 9912897, 1999; Chem. Abstr. 1999, 194117. For a
preliminary account of the in vivo effects of these compounds,
see: (d) Hartke, J . R.; J ankowsky, M. L.; deLong, M. A.; Soehner,
M. E.; J ee, W. S. S.; Lundy, M. W. Prostanoid FP Agonists Build
Bone in the Ovariectomized Rat. J . Bone Miner. Res. 1999, 14,
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L.; Soehner, M. E.; Wos, J . A.; Soper, D. L. Lundy, M. W.
Tetrahydro-fluprostenol, a 17-Phenyl Saturated Prostanoid FP
Receptor Agonist, is a Bone Anabolic Agent in the Aged, OVX
Rat. J . Bone Miner. Res. 1999, 14, Suppl. 1, S275. A complete
evaluation of the in vivo effects of this class of compounds will
be reported in due course.
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