Phenylacetamides as selective α-1A adrenergic receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00307-3

A novel class of potent and selective α-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known α-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00307-3

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1621±1624
Phenylacetamides as Selective ꢀ-1A Adrenergic Receptor
Antagonists
Michael A. Patane,a,* Robert M. DiPardo,a Randall C. Newton,a RoseAnn P. Price,a
Theodore P. Broten,b Raymond S. L. Chang,b Richard W. Ransom,b Jerry Di Salvo,c
Dhanapalan Nagarathnam,d Carlos Forray,d Charles Gluchowskid and Mark G. Bocka
aDepartment of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA
bDepartment of Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA
cBiochemistry and Physiology, Merck & Co., Inc., Rahway, NJ 07065, USA
dSynaptic Pharmaceutical Corp., 215 College Road, Paramus, NJ 07652, USA
Received 6 April 2000; accepted 22 May 2000
AbstractÐA novel class of potent and selective a-1a receptor antagonists has been identi®ed. The structures of these antagonists
were derived from truncating the 4-aryl dihydropyridine subunit present in known a-1a antagonists. The design principles which led
to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in
vivo studies are described. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
focused on identifying a suitable structural replacement for
the highly functionalized 4-aryl dihydropyridine subunit
found within known a-1a antagonists such as 1 (Fig. 1).4
Two mechanistically distinct drug classes are currently
available to physicians for the clinical management of
the urological disorder, benign prostatic hyperplasia
(BPH). They are 5a-reductase inhibitors that function
by reducing prostatic mass and thus help alleviate
mechanical constriction of the urethra, and a-1 adrenergic
receptor antagonists that act by relaxing tissue in the
lower urinary tract (LUT) and thereby facilitate urine
¯ow. Recently, the a-1 receptors have been divided into
three subclasses: the a-1A, a-1B, and a-1D.1,2 Among
these, the a-1A receptor is believed to be primarily
responsible for mediating smooth muscle contraction in
the LUT and prostate.3 While the physiological roles of
the a-1B and a-1D receptors remain to be clearly de®ned
in humans, they are associated with hypotensive e€ects
induced by nonselective a-1 receptor antagonists. There-
fore, a selective a-1A antagonist may be an ecacious
agent for the treatment of BPH and could be devoid of
ancillary cardiovascular e€ects.
Results and Discussion
Structure±activity relationships
Our plan to simplify the structures of the known 4-aryl
dihydropyridine-containing a-1a antagonists was for-
mulated based on an assessment of the structural compo-
nents housed within compound 1. Examination of 1
revealed to us that a cinnamide group was embedded
within the structure. We reasoned that excising the
dihydropyridine moiety might eliminate some of the
metabolic liabilities associated with this structural class.
We, therefore, replaced the 4-aryl dihydropyridine with
the dihydrocinnamic acid shown in 3 without altering
the remainder of the core structure. The consequence of
this modi®cation was a 67-fold decrease in a-1a binding
anity.5 Our next course of action was to complete a
systematic study that focused on varying the tether
lengths between the piperidine nitrogen and the amide N-
H and between the 4-nitrophenyl group and the amide
carbonyl (Table 1). Substituting a phenylacetamide (5)
for the dihydrocinnamide (3) produced a 4-fold potency
enhancement. Studies examining substituent e€ects on
the aryl-portion of the phenylacetamide revealed that
Our goal at the incipient stage of this work was to syn-
thesize potent and selective a-1A antagonists for the
treatment of BPH. The approach described herein
*Corresponding author. Tel.: +1-215-652-6488; fax: +1-215-652-
7310; e-mail: michael_patane@merck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00307-3

1622
M. A. Patane et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1621±1624
(8) was installed at this position, the a-1a anity
increased by >10-fold relative to 6. The potency enhan-
cing bis(4-methylphenyl)acetamide group found in 8 was
utilized in studies directed toward optimizing the amine-
portion of these antagonists.
Due to our concern about the potential metabolic gen-
eration of the known opioid ligand, nor-meperidine,6
which could form via oxidative dealkylation of the
piperidine nitrogen, our focal point shifted to alternative
4-aryl piperidines and piperazines. The structures and in
vitro binding pro®les of select examples are summarized
in Table 2. Two important discoveries emerged from
this investigation. The installation of a cyano group at
the 4-position of 4-arylpiperdines increases binding
selectivity for the a-1a receptor (9 versus 11 and 12 ver-
sus 13). Furthermore, an ortho substituent on the 4-
piperidine aryl group enhances a-1 potency (14 versus
15). These two moieties were incorporated into the
structures of the antagonists highlighted in Table 3. Two
of the ortho substituents examined, 2-methyl- and 2-
chloro-phenyl (16 and 18, respectively), further enhanced
the in vitro binding pro®les relative to the unsubstituted
phenyl analogue, 11. Overall, the in vitro pro®les of
Figure 1.
the 4-nitro and 4-methyl substituted phenyl compounds
have equivalent receptor binding pro®les (cf 5 and 6,
Table 1).
Since the 4-aryl dihydropyridine includes structural ele-
ments at the positions linking the carbonyl attachment
point and the 4-aryl group, we investigated phenylacet-
amides bearing similar forms of branching adjacent to
the carbonyl of attachment. The addition of a methyl
group on the methylene portion of the phenylacetamide
subunit in 5 provided a modest boost in a-1a binding a-
nity (7). However, when a larger group, 4-methylphenyl
Table 1. a-1 Binding data
Table 3. a-1 Binding data
Ki (nM)a
m
n
R
X
a-1a
a-1b
910
>3000
3300
>3000
1700
450
a-1d
Ki (nM)
3
4
5
6
7
8
1
0
1
1
1
1
1
1
0
0
0
0
H
H
H
NO2
NO2
NO2
Me
NO2
Me
240
380
75
74
47
1300
1500
6300
3400
1700
960
A
a-1a
a-1b
a-1d
H
Me
4-MePh
11
16
17
18
19
H
Me
CF3
Cl
7.3
1.3
22
0.99
7.5
>2000
360
1900
280
570
1400
1100
3200
660
5.1
aAll Kis are calculated for competition binding assays (I125-HEAT)
utilizing cloned human a-1 receptors (nꢀ2).5
OMe
710
Table 2. a-1 Binding data
Ki (nM)
a-1b
Ki (nM)
a-1b
A
a-1a
a-1d
A
a-1a
a-1d
8
5.1
8.8
450
960
230
12
13
14
15
27
25
12
1.1
670
>2000
23
3600
>5000
120
9
34
570
10
11
570
7.3
3300
1400
>2000
6.6
34

M. A. Patane et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1621±1624
1623
compounds 16 and 18 are improved relative to our
initial dihydropyridine lead, 1, and the molecular weight is
more than one hundred daltons lower. At this point, the
pharmacokinetics of 16 were evaluated in two species.
the phenylacetamide present in 16 might be a site of
metabolic oxidation.7 Therefore, several halo-substituted
phenylacetamides were prepared (Table 5). The 4-methyl-
and 4-chloro-phenylacetamides have comparable in vitro
binding pro®les. However, the 4-¯uorophenylacetamide
has 3-fold lower anity for the a-1a receptor relative to
24 and 25, but the 3-¯uoro- (27) and 3,4-di¯uoro-phenyl
(28) acetamides are equipotent to 24 and 25. Compounds
27 and 28 possess a-1 binding pro®les comparable to that
of the higher molecular weight bis(4-methylphenyl)ace-
tamide 16 but should be devoid of the previously
described metabolic liability.
Although the in vitro pro®le of 16 is signi®cantly improved
when compared with the initial dihydrocinnamic acid lead
structure 5, the pharmacokinetic pro®le is poor (rat:
10% F, 18 min t1=2 and dog: 4F, 60 min t1=2, Cmax420
nM at 3 mpk po). A number of basic strategies were
employed in an attempt to enhance the pharmacokinetic
pro®le of 16. One approach focused on further reducing
molecular weight and modifying potential sites of
metabolism.
The racemates, 27 and 28, were separated utilizing chiral
HPLC (Chiralcel OD column). The in vitro binding data
for one enantiomeric pair is highlighted in Figure 2. It is
clear from the data that a single enantiomer is respon-
sible for the high in vitro binding anity speci®cally for
the a-1a receptor. The more potent isomer, (+)-28, was
chosen for further characterization.
Since the optimal size for an a-substitutent at the phenyl-
acetamide methylene position remained ambiguous based
on the limited data set in Table 1, three a-alkyl phenylace-
tamides (21, 22, and 23) were prepared (Table 4). These
compounds all have similar a-1 binding pro®les, but the
isopropylphenylacetamide (23) reduces molecular weight
to the greatest extent. Therefore, the isopropylphenylacet-
amide was utilized in conjunction with the potency
enhancing groups already described in an e€ort to improve
pharmacokinetics. For example, replacement of the 4-
cyano-4-phenyl piperidine (21) with 4-cyano-4-(2-methyl-
phenyl) piperidine (24) produced a 10-fold a-1a potency
enhancement. This potency increase may be attributable
to conformational changes induced by the 2-methyl
group on the orientation of the 4-phenyl group and/or
of the piperidine ring.
When examined in counterscreens, (+)-28 was found to
be >50-fold selective against the other G-protein coupled
receptors (human a-2a, a-2b, a-2c, dopamine-1,-2,-3,-4,-5,
and 5-HT receptors) tested. The study of the functional
activity of (Æ)-28 in isolated rat prostate tissue revealed
that (Æ)-28 competitively antagonizes phenylephrine-
induced contraction with a Kb value of 110 nM. Prior to
the delineation of the stereochemistry of the preferred
enantiomer, (+)-28, the bioavailability of (Æ)-28 was
measured in rats (8% F and 120 min t1=2 at 10 mpk po/3
mpk iv) and dogs (19% F and 120 min t1=2 at 3 mpk po/1
mpk iv). Reasonable plasma levels of (Æ)-28 were detected
in both species. In particular, the high oral Cmax (1.3 uM),
Based on in vitro metabolism studies of a related com-
pound, we anticipated that the 4-methyl substituent on
Table 5. a-1 Binding data
Table 4. a-1 Binding data
Ki (nM)
Ki (nM)
A
B
a-1a
a-1b
a-1d
a-1a
a-1b
a-1d
24
25
26
27
28
Me
Cl
F
H
F
H
H
H
F
7.4
6.4
24
3.4
2.0
650
870
960
680
900
1100
1300
2400
2700
1600
20
Phenyl
i-Propyl
Cyclopentyl
Cyclohexyl
28
72
50
61
840
1200
2000
1100
3300
2900
2300
2500
(Æ)-21
(Æ)-22
(Æ)-23
F
Figure 2.

1624
M. A. Patane et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1621±1624
Scheme 1.
select pharmacokinetic studies, Carl F. Homnick for
assistance with chiral HPLC separations of enantiomers,
and Dr. Roger Freidinger.
low volume of distribution (0.79 L/kg), and moderate
clearance rate (6.7 mL/min/kg) observed in dogs represent
promising results.
Synthesis
References and Notes
The 4-aryl piperidines were synthesized utilizing a spiro-
annulation reaction of phenylacetic esters or benzylnitriles
and N-Boc-bis-chloroethylamine (Scheme 1).8 Depro-
tection, alkylation, and a second deprotection completes
the assembly of the prerequisite propyl amines. The
coupling reactions of these amines to the phenylacetic
acids were conducted utilizing standard EDCI/HOBt
conditions. The phenylacetic acids employed were either
commercially available or synthesized utilizing literature
methods.9
1. Hieble, J. P.; Bylund, D. B.; Clarke, D. E.; Eikenburg, D.
C.; Langer, S. Z.; Lefkowitz, R. J.; Minneman, K. P.; Ru€olo,
R. R. Pharmacol. Rev. 1995, 47, 267.
2. Alpha-1A, a-1B, and a-1D refer to pharmacologically
characterized receptors and a-1a, a-1b, and a-1d refer to
cloned receptors.
3. (a) Price, D. T.; Schwinn, D. A.; Lomasney, J. W.; Allen, L.
F.; Caron, M. G.; Lefkowitz, R. J. J. Urol. 1993, 150, 546. (b)
Forray, C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Shapiro, E.;
Tang, R.; Lepor, H.; Hartig, P. R.; Weinshank, R. L.; Bran-
chek, T. A.; Gluchowski, C. Mol. Pharmacol. 1994, 45, 703. (c)
Chapple, C. R.; Burt, R. P.; Andersson, P. O.; Greengrass, P.;
Wyllie, M.; Marshall, I. Br. J. Urol. 1994, 74, 585.
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M. R.; Chiu, G.; Wong, W. C.; Hong, X.; Fang, J.; Forray,
C.; Branchek, T. A.; Heydorn, W. E.; Chang, R. S. L.; Broten,
T.; Schorn, T. W.; Gluchowski, C. J. Med. Chem. 1998, 41,
5320.
5. The binding anities to the human a-1 receptors for the
synthetic compounds were measured utilizing cloned receptor
binding assays. (See ref 3b).
6. Slater, P.; Cross, A. J. In Neuropeptide Technology. Gene
Expressions and Neuropeptide Receptors; Conn, P. M., Ed.;
Academic: San Diego, 1991; Vol. 5, pp 459±478.
7. Fernandez-Metzler, C. L.; Owens, K. G.; Baille, T. A.;
King, R. C. Drug Metab. Dispos. 1999, 27, 32.
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R. A. Alpha-1a Adrenergic Receptor Antagonists, US5661163,
26 Aug 97. Chem. Abstr. 1997, 126, 131383.
Conclusion
A series of phenylacetamides has been identi®ed as
potent and selective a-1a antagonists. These antagonists
have lower molecular weights and have improved in vitro
pro®les relative to the known 4-aryl dihydropyridine-
containing a-1A antagonists. The meperidine-like group
within 1 has been replaced with 4-aryl-4-cyanopiperidines
which provided a-1a potency and speci®city enhance-
ments. For example, (+)-28 exhibits improved speci®city
for the a-1a receptor, has a lower molecular weight than 1
and displays acceptable pharmacokinetics. Based on the
data presented, a signi®cant stereochemical preference
exists for optimizing a-1a binding anity of a-alkyl
phenylacetamides.
9. (a) Takahashi, Y.; Yoneda, N.; Nagai, H. Chem. Lett.,
1985, 1733. (b) Fuji, K.; Node, M.; Tanaka, F.; Hosoi, S.
Tetrahedron Lett. 1989, 30, 2825. (c) Tanaka, F.; Node, M.;
Tanaka, K.; Mizuchi, M.; Hosoi, S.; Nakayama, M.; Taga, T.;
Fuji, K. J. Am. Chem. Soc. 1995, 117, 12159.
Acknowledgements
The authors thank Drs. Timothy V. Olah and Kelem
Kassahun for LCMS analysis of plasma samples from