Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors.

We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.

Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.

We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.

Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 1: synthesis and inhibitory activity of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides.

We synthesized and evaluated a series of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides to identify potent inhibitors of calcium-release-activated calcium (CRAC) channels with greater selectivity than voltage-operated calcium (VOC) channels. These efforts resulted in identification of compounds 22 and 24. The former exhibits highly potent and selective CRAC channel inhibitory activity, and the latter inhibited phytohemagglutinin-induced interleukin-2 production by Jurkat T lymphocytes and concanavalin A-induced hepatitis in mice.

Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 2: Synthesis and inhibitory activity of aryl-3-trifluoromethylpyrazoles.

To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.

(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.

Synthesis and pharmacological evaluation of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel specific bradycardic agents.

A series of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized, and their bradycardic activities were investigated in the isolated right atria of guinea pigs and in conscious rats. These efforts identified the achiral compound 2f, which exhibited potent and long-lasting bradycardic activity with minimal effects on mean blood pressure in conscious rats.