Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).

Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.

1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors.

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.

Structure-activity relationships of the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series of monoamine reuptake inhibitors.

The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.

3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors.

A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.

Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors.

A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).

1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators.

A series of novel 7-(5'-cyanopyrrol-2-yl) substituted benzo[1,4]oxazepin-2-ones were prepared and tested for their progesterone receptor (PR) agonist or antagonist activity in the alkaline phosphatase assay using the human T47D breast carcinoma cell line. Both PR agonists and antagonists were achieved with an appropriate choice of 5-substitution. Several analogs were potent PR agonists (e.g., 12 and 13) or PR antagonists (e.g., 18) with good selectivity over other steroid receptors.

7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists.

Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.

SAR studies of 6-(arylamino)-4,4-disubstituted-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones as progesterone receptor antagonists.

We previously disclosed that 6-aryl benzoxazin-2-ones were PR modulators. In a continuation of this work we examined the SAR of new 6-arylamino benzoxazinones and found the targets 1-25, with an extra amino linker between the pendent 6-aryl groups and benzoxazinone or benzoxazine-2-thione core, were PR antagonists. A series of compounds with substituents at the 1- and 4-positions as well as different 6-aryl groups were prepared and tested in the T47D cell alkaline phosphatase assay. Interestingly, the SAR unveiled from the 6-arylamino benzoxazinones was quite different from those of their parent compounds. For example, in contrast to the 6-aryl benzoxazinones, methyl substitution at the 1-position significantly increased the potency of 6-arylamino benzoxazinones. Several 6-arylamino benzoxazinones (e.g., 12, IC(50)=5.0 nM) had low nanomolar in vitro potency as PR antagonists in the T47D cell alkaline phosphatase assay.

Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget.

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.

SAR studies of 6-aryl-1,3-dihydrobenzimidazol-2-ones as progesterone receptor antagonists.

We have previously reported that the aryl substituted benzimidazolones, benzoxazinones, and oxindoles (e.g., 1-3) are progesterone receptor (PR) antagonists and have recently disclosed that the nature of 5- and 6-aryl moieties played a critical role in PR functional activity in the oxindole and benzoxazinone templates. For example, replacing the phenyl group of PR antagonists 2 and 3 with a 5'-cyanopyrrol-2'-yl moiety switched their functional activity to PR agonist activity (2a and 3a). These findings prompted us to examine if there is a similar effect of the 6-aryl moieties on the PR functional activity for the benzimidazolone template. Numerous analogs, such as 5, showed potent PR antagonist activity with about a 10-fold increase in potency as compared to those reported earlier in the same series. More interestingly, pyrrole-containing benzimidazolones 24-27 remained as PR antagonists in contrast to the PR agonist activity switch for oxindole and benzoxazinone scaffolds when a 5'-cyanopyrrol-2'-yl group was installed as a pendant aryl group.

Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.

The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.

6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists.

Novel 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones were synthesized and tested as progesterone receptor (PR) antagonists. These compounds were potent and showed good selectivity for PR over other steroid receptors such as the glucocorticoid and androgen receptors (e.g., greater than 80-fold selectivity at PR for 4h). Numerous 6-aryl benzoxazinones (e.g., 4h-j) were active orally in the uterine decidualization and component C3 assays in the rats. In these in vivo models,4h had potencies comparable to mifepristone.

Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.

Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).