De novo design of a novel oxazolidinone analogue as a potent and selective α(1A) adrenergic receptor antagonist with high oral bioavailability

Full text of DOI:10.1021/jm000085e

© Copyright 2000 by the American Chemical Society
Volume 43, Number 15
J uly 27, 2000
Communications to the Editor
Ch a r t 1
De Novo Design of a Novel Oxa zolid in on e
An a logu e a s a P oten t a n d Selective r1A
Ad r en er gic Recep tor An ta gon ist w ith
High Or a l Bioa va ila bility
Bharat Lagu,*,† Dake Tian,† Yoon J eon,† Chao Li,†
J ohn M. Wetzel,† Dhanapalan Nagarathnam,†
Quanrong Shen,† Carlos Forray,‡
Raymond S. L. Chang,| Theodore P. Broten,|
Richard W. Ransom,| Tsing-Bao Chan,|
Stacey S. O’Malley,| Terry W. Schorn,|
A. David Rodrigues, Kelem Kassahun,
Douglas J . Pettibone,| Roger Freidinger,§ and
Charles Gluchowski†
Departments of Chemistry and Pharmacology,
Synaptic Pharmaceutical Corporation, 215 College Road,
Paramus, New J ersey 07652, and Departments of Medicinal
Chemistry, Pharmacology, and Drug Metabolism, Merck
Research Laboratories, West Point, Pennsylvania 19486
Received February 25, 2000
A number of R1A subtype-selective antagonists rep-
resenting different structural classes of compounds such
as SNAP 5089 (dihydropyridine),6 GG818 (oxazole),7 and
A-131701 (benz[e]isoindole)8 have been reported in the
literature over the past few years. We have recently
reported that the dihydropyrimidinones, represented by
general structure 1 (Chart 1), show subnanomolar
binding affinity for R1A with greater than 300-fold
selectivity over R1B, R1D, and R2 adrenoceptors.9,10 Many
of these compounds, however, show marginal bioavail-
abilities (0-30%) and short plasma half-lives (<4 h) in
rats and dogs. Modification of the piperidine moiety or
the linker portion (-CONHCH2CH2CH2-) did not im-
prove the pharmacokinetic profile of the resulting
compounds.10 Therefore, we decided to replace the
dihydropyrimidinone moiety in 1 with another hetero-
cycle by utilizing the known structure-activity relation-
ship (SAR) in the dihydropyrimidinone series. The SAR
for 1 reveals that (1) the chiral center at the C-4 position
of the dihydropyrimidinone is important for the ob-
served binding affinity for the R1A receptor, (2) a number
of modifications at the C-5 and C-6 positions of the
In tr od u ction . Benign prostatic hyperplasia (BPH),1
a urological disorder which results in obstruction to
urine flow, is currently treated with a number of non-
subtype-selective R1 adrenoceptor antagonists such as
terazosin,2 doxazosin,3 and tamsulosin.4 These clinical
agents, however, are associated with a number of
cardiovascular side effects such as postural hypotension,
presumably via blockade of vascular R1 adrenergic
receptors in addition to the prostatic R1 adrenoceptors.
It has been postulated that selective blockade of the R1A
adrenoceptor, the predominant R1 receptor in the pros-
tate, could provide symptomatic relief of BPH without
the need for the dose titration which is required for
several of the nonselective R1 antagonists.5
* To whom correspondence should be addressed. Present address:
R. W. J ohnson PRI, Rte 202, P.O. Box 300, Raritan, NJ 08869. Tel:
908-704-4291. Fax: 908-526-6469. E-mail: blagu@prius.jnj.com.
† Department of Chemistry, Synaptic Pharmaceutical Corp.
‡ Department of Pharmacology, Synaptic Pharmaceutical Corp.
§ Department of Medicinal Chemistry, Merck Research Laboratories.
| Department of Pharmacology, Merck Research Laboratories.
Department of Drug Metabolism, Merck Research Laboratories.
10.1021/jm000085e CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/07/2000

2776 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15
Communications to the Editor
Sch em e 1a
a
(a) H2, Pd-C, MeOH, 95%; (b) 3-bromopropylphthalimide, K2CO3, DMF, 88%; (c) hydrazine, MeOH, reflux, 93%; (d) t-BuLi, THF,
CH3CHO; (e) CH3ONH2‚HCl, MeOH, 68% for two steps; (f) Boc2O, CHCl3, 91%; (g) NaH, THF, 89%; (h) separation of the diastereomers
by column chromatography and separation of the enantiomers by chiral phase HPLC, 16%; (i) n-BuLi, THF, 4-nitrophenyl chloroformate,
75%; (j) 5, THF, 89%.
Ta ble 1. Binding Affinity Profile of 3 for Recombinant
dihydropyrimidinone are tolerated, suggesting a less
Receptors and Tissue Preparations
critical role for the substituents at these positions in
assay
radioligand
125H]HEAT
Ki (nM)a
selectb
achieving an optimum binding and selectivity profile,
and (3) the hydrogen on the N-1 of the dihydropyrimi-
dinone can be replaced without significant loss in
binding affinity for the R1A receptor.11 We envisioned
the replacement of the dihydropyrimidinone with an
oxazolidinone moiety 2, where the chiral center from 1
is maintained, the C-5 carbon atom is extruded, and the
nitrogen at the 1-position is replaced with an oxygen
atom. In this Communication, we describe the synthesis
of such a novel oxazolidinone (3, SNAP 7915) and the
in vitro and in vivo profile of this compound.
Ch em istr y. The synthesis of compound 3 is depicted
in Scheme 1. Commercially available 4-(4-fluorophenyl)-
1,2,3,6-tetrahydropyridine hydrochloride (4) was con-
verted into 3-[4-(4-fluorophenyl)piperidin-1-yl]propyl-
amine (5) by a three-step sequence in high yield. The
vicinal amino alcohols 7a -d synthesized from 6 by a
known procedure12 were cyclized into oxazolidinones
8a -d via a two-step process. The trans isomers 8a ,b
(in which the protons at the C-4 and C-5 positions of
the oxazolidinone ring are in trans spatial orientation)
were separated from the cis isomers 8c,d by column
chromatography. The relative stereochemistry was as-
signed using the NOE observed between the C-4 and
C-5 protons. The two enantiomers of the trans-oxazoli-
dinone were resolved by chiral phase HPLC.13 The (+)-
trans enantiomer 8a , which was found to possess 4S,5S
absolute stereochemistry,14 was treated with n-BuLi and
the resulting solution was converted to the p-nitrophen-
yloxycarbonyl derivative 9 in 75% yield. Treatment of
9 with amine 5 led to formation of the desired product
3 in high yield.
human R1A/R1B/R1D
[
[
[
0.17 ( 0.03/119 ( >700
24/122 ( 6
dog R1A/R1B/R1D
rat R1A/R1B/R1D
125H]HEAT
125H]HEAT
0.23 ( 0.01/121 ( >500
13/133 ( 8
0.36 ( 0.09/79 (
14/62 ( 9
>200
human R2A,2B,2C
rat L-type
[3H]rauwolscine >45
>250
>5000
[3H]nitrendipine >1000
Ca-channelc
H1 (human brain)c [3H]pyrilamine
human H2
5-HT1A,1B,1D,2A
54 ( 27
>1000
>500
>200
>5000
>1000
[3H]tiotidine
[3H]serotonin
a
Ki values obtained using radioligands in competition binding
b
assays with recombinant receptors unless otherwise noted. Se-
lectivity ) Ki for other receptor/Ki for R1A receptor. c Tissue
preparation.
(0.36 and 0.23 nM, respectively), indicating no signifi-
cant species difference in the R1 binding of 3. Compound
3 did not show significant affinity for the rat L-type
calcium channel and a number of G-protein coupled
receptors such as R2 adrenergic, histamine, and sero-
tonin receptors (Table 1).16-22 In addition, compound 3
did not exhibit significant cross-reactivity when screened
against a panel of more than 30 G-protein coupled
receptors.23 The binding affinity and selectivity of 3 for
the R1A receptor are similar to those observed for a
number of dihydropyrimidinones such as 1.9,10
The comparison of functional potency of the R1A
-
selective antagonist 3 and the nonselective R1 antagonist
terazosin in a number of in vitro and in vivo assays is
shown in Table 2.24 Compound 3 potently antagonized
A-61603-25 or phenylephrine-induced contraction of hu-
man, dog, and rat prostatic tissues. It is important to
note that the antagonist potencies (Kb ) 0.1-0.33 nM)
observed for 3 in the functional assays were in close
agreement with the binding affinities (Ki ) 0.17-0.36
nM) for the cloned human, dog, and rat R1A receptors.
In anesthetized rats, compound 3 showed higher
functional potency (AD50 ) 12 µg/kg) to inhibit the
phenylephrine-induced contractile response of the in
Resu lts a n d Discu ssion . Compound 3 showed sub-
nanomolar (0.17 nM) binding affinity for the recombi-
nant human R1A adrenoceptor and greater than 700fold
selectivity over R1B and R1D receptors in competition
binding assays using [125I]HEAT (Table 1).15 High
binding affinity for the R1A adrenoceptor was also
observed for the rat and dog recombinant R1 receptors

Communications to the Editor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2777
Ta ble 2. In Vitro and in Vivo Functional Profiles and
Pharmacokinetics for 3 and Terazosin
significantly lower dose of 3 (3 µg/kg) compared to
terazosin (16 µg/kg) was required to block the effect of
phenylephrine. These observations support the hypoth-
esis that an R1A-selective antagonist may be able to
provide symptomatic relief for BPH patients while
causing fewer cardiovascular side effects.
assay
agonist
3
terazosin
Kb human prostate (nM) A-61603
0.1 ( 0.035
25 ( 2.7
130 ( 33
25 ( 3
19 ( 2.4
52 ( 15
Kb dog prostate (nM)
Kb rat prostate (nM)
Kb rat aorta (nM)
AD50 in situ rat
phenylephrine 0.33 ( 0.05
A-61603
0.26 ( 0.13
norepinephrine >1000
phenylephrine 12 ( 1.8
Compound 3 exhibited significantly improved oral
bioavailability and plasma half-life in rats (25% and 6
h) and dogs (74% and >12 h) compared to the dihydro-
pyrimidinones represented by 1 (oral bioavailability <
25% and half-life < 6 h in rats and dogs).
On the basis of its high binding affinity and selectivity
for the R1A adrenoceptor, its unique structure, and its
excellent pharmacokinetic and pharmacodynamic prop-
erties, compound 3 (SNAP 7915) has emerged as one of
the most interesting R1A antagonists reported to date.
prostate (µg/kg)
Kb dog IUPa (µg/kg)
phenylephrine 3.0
phenylephrine >300
16
72
b
DBP15
,
dog (µg/kg)
rat: F, t1/2 (h)
dog: F, t1/2 (h)
25%,c 6.0 ( 1.2 49%, 7.5
74 ( 17%,d >12
a
b
Intra-urethral pressure. DBP15 is the dose of a compound
required to cause a drop of 15 mmHg in diastolic blood pressure.
c No SD available. Oral bioavailability was calculated using mean
oral AUC values. iv: 1 mg/kg dose (n ) 4), AUC ) 559 ( 139
ng‚h/mL; po: 3 mg/kg dose (n ) 4), AUC ) 419 ( 128 ng‚h/mL.
d
iv: 1 mg/kg dose (n ) 3), AUC ) 2274 ( 488 ng‚h/mL; po: 3
mg/kg dose (n ) 3), AUC ) 4900 ( 320 ng‚h/mL; the values are
mean ( SD.
Ack n ow led gm en t. We thank Drs. Robert Taber and
William Heydorn (Synaptic Pharmaceutical Corp.) for
their encouragement. We thank Mr. Boshan Li, Mr.
Vincent J orgenson, Mr. Yong Zeng (Synaptic Pharma-
ceutical Corp.), and Ms. Linda Payne (Merck Research
Laboratories) for technical assistance and Dr. Mark
Bock (Merck Research Laboratories) for helpful discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 3 and other intermedi-
ates. This material is available free of charge via the Internet
at http://pubs.acs.org.
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(Kb > 1 µM) relative to its potency to inhibit agonist-
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J M000085E