Bioorganic & Medicinal Chemistry Letters 12 (2002) 2411–2413
Non-Steroidal Pregnancy-Terminating Agents: Design,
Synthesis and Structure–Activity Relationships of
2-Aryl-1,2,4-triazolo[1,5-a]pyridine
Tao Liu and Yongzhou Hu*
Zhejiang University, Department of Medicinal Chemistry, College of Pharmacy, Hangzhou 310031, PR China
Received 28 January 2002; accepted 21 May 2002
Abstract—The syntheses and the pregnancy-terminating activity relationships of compounds 5a–n are reported. Compounds 5b and
5l are found to be more potent than DL-111—a known drug having effective pregnancy-terminating activity in vitro. Further
research shows compounds 5b and 5l have the same activity as DL-111 in vivo. We also found an exciting result that they have
excellent anti-implantation activity after oral administration. # 2002 Elsevier Science Ltd. All rights reserved.
In a search for new nonhormonal compounds with
antifertility activity, a series of 2-aryl-1,2,4-triazolo-
[5,1-a]isoquinoline 2-aryl-1,3-midazolo[2,1-a]isoquinoline
were synthesized by Italian researchers during the
1980s. They found these compounds had some early
pregnancy-terminating activity;1À5 in particular, L14105
1 and DL-111 2 had stronger activity, with ED50 values
of 0.016 and 0.04 mg/kg/day in hamster, respectively.4
Research testifies that the mechanism of early preg-
nancy-terminating role of DL-111 is to induce apoptosis
to cause a luteolytic effect in pregnant rats.6 But their
very sustained pharmacokinetic profiles and/or their
low solubility, even in oily vehicles, hindered their use in
clinical studies. In order to develop new triazole com-
pounds that have high potency, reduced toxicity and
good solubility, it is worth further investigation to
modify the structure of the lead compound—L14105.
analysis and 2-phenyl ring can improve the activity.4
However, the isoquinoline ring as a possible pharmaco-
phore is still not well understood. In this paper,
we describe the synthesis and biological properties of
2-aryl-1,2,4-triazolo[5,1-a]pyridines. The pattern of the
isoquinoline ring was substituted by 2-methyl- or
4-methylpyridine to decrease the partition coefficient
and the substituent of 2-phenyl was changed to increase
the stability of metabolism.
The synthesis of target compounds is shown in Scheme 1.
N-Amination of 2-methylpyridine or 4-methylpyridine 3
with O-mesitylenesulfonyl hydroxylamine (MSH) affor-
ded N-amine-2-methylpyridinium mesitylenesulphonate
or N-amine-4-methylpyridinium mesitylenesulphonate
4. Subsequently, condensation of N-amine salts 4 with
substituted benzonitrile in alkaline conditions gave the
desired compounds 5a–n, respectively (Table 1).
Newly synthesized compounds were tested for potency
as early pregnancy-terminating agents. In vitro early
pregnancy-terminating activity was tested to see whe-
ther they could induce apoptosis to cause a luteolytic
effect. It revealed that one mechanism of early preg-
nancy-terminating activity of DL-111 was the action of
luteolysis in the study of Bo Yang.6 Corpora lutea
which were excised frompseudopregnant rats were dis-
sected out under a microscope and seeded at a density
of (1–2)Â105 cells/well in 0.5 mL McCoy’s 5A medium
supplemented with 0.1% BSA for 24 h, then tested
compounds were added. Cells were cultured at 37 ꢀC in
5% CO2 for 24 h. Cell viability was assessed by trypan
Research indicates that the ring of triazole is essential for
the pregnancy-terminating activity through structural
*Corresponding author. Tel.: +86-571-8721-7210; fax: +86-571-
8721-7412; e-mail: huyz@zjuem.zju.edu.cn
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00399-2
Liu, Tao
