The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)--dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (K = 1.0-2.8 nM), rat forebrain (K = 4.2 nM), and human platelets (K = 2.6-3.3 nM). Valbenazine (K = 110-190 nM) and NBI-136110 (K = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT, 5-HT, 5-HT) or dopamine (D or D) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].

Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.

Limited data are available on the attitudes of gynecologists regarding mode of hysterectomy for benign indications. This cross-sectional study used a postal questionnaire to assess attitudes of members of the Swedish Society of Obstetrics and Gynecology toward mode of benign hysterectomy. The choices of mode of hysterectomy were total abdominal hysterectomy, subtotal abdominal hysterectomy, laparoscopic or laparoscopically-assisted hysterectomy, and vaginal hysterectomy (VH). Participants were asked questions about their gender, seniority, place of work, and surgical experience, including years in the specialty and annual number of hysterectomies performed to determine whether differences in such factors influenced their choice of mode. The gynecologists were asked to choose between these modes for 3 scenarios with different benign clinical conditions. Scenario A was a normal to slightly enlarged uterus with no uterine descensus and no previous cervical dysplasia. Scenario B differed from the first scenario only in that there had been previous treatment of cervical dysplasia up to moderate degree (CIN II). In scenario C, there was an enlarged uterus (larger than gestational week 12-13) with no uterine descensus and no previous cervical dysplasia. The respondents were also asked to give their personal view of how the overall distribution should be for the different modes of benign hysterectomy. Multiple logistic regression and multivariate models of covariance were used for unadjusted and adjusted analyses.The participants chose VH in general or when the uterus was of normal size or slightly enlarged (scenarios A and B), and recommended abdominal hysterectomy and subtotal abdominal hysterectomy when the uterus was enlarged (scenario C). More male gynecologists than female gynecologists favored VH as a personal preference. There were significant variations in choice and suggested distribution of mode for place of work, seniority, and annual number of hysterectomies performed. More than 50% of the participants recommended the minimally-invasive methods of vaginal and laparoscopic hysterectomy as their overall personal choice for suggested distribution.These findings indicate that choice of mode of hysterectomy for benign conditions among gynecologists is significantly influenced by personal preference based on differences in gender, place of work, seniority, and annual number of hysterectomies, and does not appear to strictly follow evidence-based recommendations. EDITORIAL COMMENT(Hysterectomy is one of the most common operations done in the United States. These days there is quite a variety of techniques for hysterectomy and we have discussed the advantages of one approach or another on these pages many times. As I analyze the results of this article on hysterectomy preferences from Sweden, I think there are 3 different levels of preferences for types of hysterectomy:(1) what is your "theoretical" preference? (this study, where you respond to a hypothetical scenario);(2) what is your "actual" practice? (what was t...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Human microdosing studies with novel drug candidates offer an opportunity to evaluate their pharmacokinetic (PK) behaviour early in drug development and before committing to the expense of clinical Phase I-enabling activities.• Such studies assume linearity of exposure with dose all the way down to a subtherapeutic dose. • Previous studies have reported partial success in the use of this technique for assessing human PK of marketed drugs. WHAT THIS STUDY ADDS• The present study describes the application of the microdosing concept in early drug development for an H1 antagonist programme where having good estimates of human PK and information about the shape of the concentration-time curve was critical for compound selection.• Microdosing data were generated for four novel compounds and one reference compound, and the data were used for advancing the compound with the most favourable PK properties. • To our knowledge, this is the first example of the use microdosing technique for compound selection. AIMSTo evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODSFive H1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTSThe median clearance (CL), apparent volume of distribution (Vd) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h -1, 302 l and 9.3 h, and the oral Cmax and AUC0-• were 0.195 ng ml -1 and 1.52 ng h ml, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONSHuman microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.

Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.