Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.

Article abstract of DOI:10.1016/S0960-894X(99)00696-4

A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

Full text of DOI:10.1016/S0960-894X(99)00696-4

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1625±1628
Selective ꢀ1a Adrenergic Receptor Antagonists Based on
4-Aryl-3,4-dihydropyridine-2-ones
Philippe G. Nantermet,a,* James C. Barrow,a Harold G. Selnick,a Carl F. Homnick,a
Roger M. Freidinger,a Raymond S. L. Chang,b Stacey S. O'Malley,b Duane R. Reiss,b
Theodore P. Broten,b Richard W. Ransom,b Douglas J. Pettibone,b Timothy Olahc
and Carlos Forrayd
aDepartment of Medicinal Chemistry, Merck & Co., Sumneytown Pike, West Point, PA 19486, USA
bDepartment of Pharmacology, Merk & Co., Sumneytown Pike, West Point, PA 19486, USA
cDepartment of Drug Metabolism, Merck & Co., Sumneytown Pike, West Point, PA 19486, USA
dSynaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ 07652-1431, USA
Received 25 October 1999; accepted 10 December 1999
AbstractÐA series of a1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in
the low nanomolar to picomolar range along with high selectivity was obtained. In vivo ecacy in a prostate contraction model in
rats was observed with a few derivatives. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
losin, although only slightly selective for the a1a
receptor subtype, has shown a better tolerability pro®le
than nonselective compounds when used to treat BPH.7
The search for more selective antagonists may thus
provide agents completely devoid of cardiovascular side
e€ects.
Benign prostatic hyperplasia (BPH), which is character-
ized by an enlargement of the prostate resulting in
urinary obstruction, is a common condition1 in males
over the age of 50. Increased prostatic mass can be
clinically treated with 5-a-reductase inhibitors, such as
®nasteride,2 thus blocking the conversion of testoster-
one to dihydrotestosterone3 which is found in excess in
the enlarged prostate. a1 Receptor antagonists such as
terazosin,4 originally developed as antihypertensive
agents, have been used for treating BPH (relaxation of
prostatic and urethral adrenergic tone), but with hypo-
tensive side e€ects. Recent pharmacological and binding
studies followed by cloning experiments have indicated
the existence of three subclasses of a1 receptors: a1a, a1b
and a1d.5 Distribution of a1 receptor subtypes among
tissues is heterogeneous and it was later shown that
the a1a receptor is the major subtype in prostatic
tissue while less prevalent in cardiovascular tissues.6
Selective a1a receptor antagonists should, therefore,
have a better therapeutic index with regard to cardio-
vascular side e€ects for the treatment of BPH. Tamsu-
Previous studies from our laboratories and others have
shown that compounds such as 1, incorporating a
4-aryl-5-carboxamide-dihydropyrimidinone (DHP) het-
erocyclic moiety are selective a1a receptor antagonists
(Fig. 1).8 The unsubstituted DHP derivatives (R1,
R2=H) generally demonstrated a poor pharmacokinetic
pro®le, which was originally attributed to poor
absorption due to the fairly high polarity (log P<1) of
these compounds. SAR studies around the DHP series
have led us to propose a pharmacophore model 2 as a
working hypothesis. A locked sp3/sp2 con®guration at
C4-C5, which insures the proper orientation between
the C4 aryl group and the C5 carboxamide, seemed
to be an important feature regarding potency.8 Accord-
ing to these results the replacement of the N-3 of
DHP by a methylene unit should ®t the pharmacophore
model and may be advantageous regarding potency,
selectivity,9 and pharmacokinetic pro®le (increased
log P) of the resulting dihyropyridinone derivatives of
type 3.
*Corresponding author. Tel.: +1-215-652-0945; fax: +1-215-652-
7310; e-mail: philippe_nantermet@merck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00696-4

1626
P. G. Nantermet et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1625±1628
Figure 1.
Chemistry
4 was also resolved by preparative chiral HPLC14 and
the ( ) enantiomer, identi®ed as the `active' enantiomer,15
was utilized for the direct preparation of the 4R amides.
The dihydropyridinone ring was prepared10±12 from 3,4-
di¯uorobenzaldehyde in racemic form, as shown in
Scheme 1. Optional methylation at N-1 followed by
hydrogenolysis of the benzyl ester provides the acid
derivatives 5 and 6, which are readily coupled to various
amines (Scheme 2) under standard conditions. The
racemic amides 14, 15, 18, 19, 22 and 23 were resolved
by preparative chiral HPLC.13 In each case the ( )
enantiomer was signi®cantly more active than the (+)
enantiomer and was assigned as R, by analogy with
previous DHP derived antagonists.8 Dihydropyridinone
A general preparation of the amines to be coupled to
the dihydropyridinone moiety is presented in Scheme 2.
Various aryl zincates were prepared from the corre-
sponding aryl halides and coupled to tri¯ate 9.8 Intro-
duction of the propylamine chain via alkylation or
reductive amination gave access to piperidines 10.
Piperidines 11 containing a 4-cyano substituent in addi-
tion to the 4-aryl group were derived from phenylace-
tonitriles and bis-(2-chloroethyl)-Boc-amine.
Scheme 1.
Scheme 2.

P. G. Nantermet et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1625±1628
1627
Table 1. Primary screen/in vitro data
Ki (nM)
1a, a1b, a1d
Ki (nM)
a1a, a1b, a1d
Compound no.
a
Compound no.
12
42, >2000, >5000
13
257, >2000, >5000
R1=H, R2=H
14
16
18
20
22
0.4, 37, 200
0.2, 100, 150
1.8, 1040, 1050
1.4, >2000, >5000
1, 805, 588
15
17
19
21
23
0.7, 54, 250
0.8, 366, 590
1.9, 425, 880
7, >2000, >5000
1.1, 842, 1155
R1=H R2=CN
R1=CN, R2=H
R1=CN, R2=CN
R1=CN, R2=F
R1=H
R1=CN
24
26
1, 330, 330
3.2, >2000, >5000
25
27
3, 1200, 682
13, >2000, >5000
Results
t1/2 for 16 and 17 (4.8 and 1.4 h respectively) does not
correlate well with the observed pharmacodynamic
duration. In the dog, bioavailabilty was improved only
for 16 (34%). Short half-lives (<1 h) and low biovail-
ability for compounds 19, 22, 23 con®rmed the poor
pharmacokinetic pro®le within this series. Metabolism
and absorption studies within the related DHP series
have suggested rapid N-dealkylation of the piperidine.8
It is possible that a ®rst pass e€ect is the reason for low
bioavailability within both series.
The proposed N to methylene substitution in the DHP
moiety was indeed tolerated. Table 1 shows the potency
of a series of dihydropyridinone derived amides against
the three subclasses of a1 receptors. As observed in the
DHP series,8 N1-methylation slightly increases selectiv-
ity against a1a while potency is only slightly diminished.
The choice of amines to be coupled to the central dihy-
dropyridinone moiety was guided by previous results in
the DHP series8 and indeed, the SAR is very similar in
both series. Introduction of a 2-¯uoro substituent on the
aryl-piperidine results in slightly increased potency and
selectivity while a 2-cyano substituent improves selec-
tivity drastically. The 4-cyano-4-(2-pyridyl)piperidine
derivatives were found to be very selective but of mar-
ginal potency. Placement of ¯uorine at the aryl 4-posi-
tion improves potency with little e€ect on the selectivity.
Introduction of an angular 4-cyano group on the piper-
idine was bene®cial to selectivity but at the expense of
potency. The best combination is illustrated by com-
pounds 16 and 17 with Ki against the a1a receptor sub-
type of 0.2 and 0.8 nM, respectively, and with selectivity
against the other subtypes greater than 450 Â.
In conclusion, a series of potent and selective a1a recep-
tor antagonists derived from a 4-aryl-3,4-dihydropyri-
dine-2-one heterocycle was uncovered. In vivo ecacy
was observed along with moderate pharmacodynamic
duration in a few cases, setting the stage for further
studies in this series.
Table 2. Selectivity screen/in vivo ecacy
Compound no.
Ki (nM)
1a, a2a, a2b, a2c
insrpa
a
hH1 AD50 (mg/kg)b/dur.c
A selection of the most active and selective antagonists
was screened against the a2 receptor subtypes and the
human histamine type I (hH1) receptor (Table 2): while
selectivity within the a receptor subclass is still very
good for both NH and N-Me derivatives, selectivity
against hHl is marginal for NH derivatives. Most of
these compounds were evaluated in vivo in an in situ rat
prostate model.16 The most active compounds remain
16 and 17 with AD50, of 5 and 9 mg/kg respectively, and
with duration of action of 2.5 and 4 h, respectively
(Tamsulosin: 3 mg/kg/3.5 h). Rat oral bioavailability for
compounds 16 and 17 was found to be low. Further, the
14
16
17
18
19
20
21
22
23
0.4, 229, 162, 313
0.2, 1288, 145, 1479
0.8, 4519, 288, 3846
1.8
1.9, 1862, 776, 1096
1.4, 7852, 676, 4677
7, 13646, 1758, 6531
1, 1972, 531, 1995
1.1, 3388, 955, 1905
19
58
398
63
355
91
616
108
302
32
5/2.5 h
9/4 h
25
17/1.5 h
29/l h
aIn situ rat prostate model.
bDose of compound required to inhibit the prostate contractile
response by 50% after challenge with the selective a1a agonist A61603.
cDuration of action in hours, after repeated challenge with the agonist.

1628
P. G. Nantermet et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1625±1628
7. Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H. J.
Urol. 1990, 144, 908.
Acknowledgements
8. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K.
L.; Rittle, K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.;
Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss, D.;
Broten, T.; Chang, R. S. L.; O'Malley, S. S.; Olah, T.; Leppert,
P.; Nagarathnam, D.; Forray, C. J. Med. Chem. submitted.
9. Within the DHP series,8 substitution at N-1 (R=Me,
COMe, CO2Me) resulted in improved selectivity and increased
pharmacodynamic duration, while substitution at N-3 led to
reduced potency and selectivity.
The authors wish to thank Kristen L. Glass, Kenneth E.
Rittle, Thomas G. Steele, Jennie B. Nerenberg, Jill M.
Erb, Catherine M. Wiscount, Ben E. Evans, Kevin F.
Gilbert, Paul Kling, Robert Bendesky, Joan D. Ellis and
Andrea Barrish for technical assistance, Nancy N. Tsou
and Richard G. Ball for X-ray crystallography analysis
and Mark G. Bock for valuable discussions during the
preparation of this manuscript.
10. Morales, A.; Ochoa, E.; Suarez, M.; Verdecia, Y.; Gonzalez,
L.; Martin, N.; Quinteiro, M.; Seoanne, C.; Soto, J. J. Het-
erocyclic Chem. 1996, 33, 103.
11. Verdecia, Y.; Suarez, M.; Morales, A.; Rodriguez, H.;
Ochoa, E.; Gonzalez, L.; Martin, N.; Quinteiro, M.; Seoanne,
C.; Soto, J. J. Chem. Soc., Perkin Trans. 1 1996, 947.
12. Svetlik, J.; Goljer, I.; Turecek, F. J. Chem. Soc., Perkin
Trans. 1 1990, 1315.
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13. Chiralpak AD 250Â20 mm at 6 mL/min or Chiralcel OJ
250Â20 mm at 8 mL/min, 15 to 35% EtOH in hexane con-
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15. Originally, (+) 4 was converted to (+) 14, the less active
enantiomer, thus identifying ( ) 4 as the enantiomer leading
to more active enantiomers ( ) 12±27. Additionally, hydro-
genolysis of (+) 4 followed by coupling with (S)-( )-a-
methylbenzylamine provided material suitable for X-ray crys-
tallography. The structure results con®rmed the S con®guration
at C4 for (+) 4 and, by default, the R con®guration for ( ) 4.
16. The prostate of anesthetized rats is connected to a force
transducer and compounds administered iv, are evaluated for
inhibition of contractile response induced by the selective a1
agonist A61603. Duration of action is obtained from repeated
challenges with the agonist. For details see ref 8.
6. Forray, C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Shapiro,
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