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

The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in vitro screens to select for compounds that are mechanistically distinct from tamoxifen and raloxifene in an effort to define the properties of an ER modulator required for bone protection. Using this approach, we identified a novel high affinity ER antagonist, GW5638, which when assayed in vitro functions as an ER antagonist, inhibiting the agonist activity of estrogen, tamoxifen, and raloxifene and reversing the "inverse agonist" activity of the pure antiestrogen ICI182,780. Thus, GW5638 appears to function as an antagonist in these in vitro systems, although in a manner distinct from other known ER modulators. Predictably, therefore, GW5638 alone displays minimal uterotropic activity in ovariectomized rats, but will inhibit the agonist activity of estradiol in this environment. Unexpectedly, however, this compound functions as a full ER agonist in bone and the cardiovascular system. These data suggest that the mechanism by which ER operates in different cells is not identical, and that classical agonist activity is not required for the bone protective activity of ER modulators.

Although TRPV4 represents an ideal molecular trigger for ciliary modulation, absent expression of the channel in ciliated cells precludes this function. However, altered expression of the channel in CRS and presumed expression of TRPV4 in secretory cells of the mucosa indicate a potential role in mucus homeostasis and CRS pathogenesis.

Objective.To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics.Methods.In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required.Results.Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30–100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg.Conclusion.Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868)

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