The female sex hormone estradiol (1) has a variety of beneficial and detrimental effects in women.' The triphenylethylene class of non-steroidal estrogens (e.g., tamoxifen, 2) shows tissue-dependent expression of estrogen agonist and antagonist activity and may represent a significant advance over conventional hormone replacement therapy with 1 for prevention of osteoporosis and cardiovascular disease in postmenopausal women2 ( Figure 1). The estrogen receptor is a ligand-activated transcription factor that belongs to the steroidbetinoid family of DNA-binding intracellular receptors (ICR). Studies with deletion and point-mutated receptors have revealed two independent transcription activation domains (AF-1 and AF-2, Figure 2) within the receptor that allow the expression of cell-and promoter-specific agonist activity in transient cotransfection experiments in vitr0.3 The translation of these observations to the design of ligands for ICRs that show tissue-specific expression of functional activity is at the forefront of modern endo~rinology.~ For this purpose, we formulated the hypothesis that the tissueselective profile of 2 was due to induction of a unique receptor conformation5 in which the antagonist activity in some tissues was due to disruption of AF-2, mediated by a H-bond interaction6 with the receptor protein in the region of the putative AF-2 a -h e l i~,~~~~ and the agonist activity in other tissues was a result of a functional AF-1 domain.3bld Combining this hypothesis with analysis of the in vitro and in vivo pharmacology of non-steroidal estrogens: it was proposed that the stilbene portion of 2 was required for AF-1 activity leading to agonist activity in bone, and the ethanolamine side chain was responsible for blocking AF-2 activity leading to antagonism in the uterus. We report here on the use of this hypothesis to identify triphenylethylene estrogens that show full agonist activity in bone through inhibition of bone loss in ovariectomized rats but which are antagonists in the rat uterus with minimal residual agonist activity.We elected to synthesize analogs of the triphenylethylene 2 in which the ethanolamine side chain was replaced by alternate H-bond acceptor groups and the degree of conformational freedom was reduced. Following the general synthetic strategy of Millerg for synthesis of (2)-tamoxifen, bromide 3 was coupled with arylboronic acid

ObjectivesThe ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS).MethodsPatients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety.ResultsBaseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints.The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred.ConclusionsThe ALIGN study shows that IL-6Rα blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile.

Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.

A series of modifications were made to the C-3 substituent of the 1,5-benzodiazepine CCK-A agonist 1. Replacement of the inner urea NH and addition of a methyl group to generate a C-3 quaternary carbon resulted in acetamide 6, which showed CCK-A receptor binding selectivity and sub-micromolar agonist activity in vitro. Benzodiazepine 6 was active in an in vivo mouse gallbladder emptying assay and represents a novel orally active, binding selective CCK-A agonist.

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