Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist.

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.

ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly.

CONTEXT: Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. OBJECTIVE: This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine. METHODS: A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected. RESULTS: Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN]; P = .6285; GH = -0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported. CONCLUSION: These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.

Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers.

PURPOSE: Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. METHODS: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. RESULTS: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. CONCLUSIONS: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. TRIAL REGISTRATION: NCT03276858, registered September 8, 2017, retrospectively registered.

COVID-19: A gender-biased pandemic.

The world today is in the midst of its second wave of the coronavirus disease 2019 (Covid-19), which started as an outbreak first reported in December 2019, Wuhan City, the capital of Hubei Province in China. Then soon enough, it was declared as a public health emergency of international concern on January 30, 2020 by WHO and a pandemic on March 11, 2020. While initially greater emphasis was laid on the elderly and people with co-morbidities such as diabetes mellitus, hypertension, obesity, and immune-compromised states as being at high risk of contracting the Covid-19 disease and/or dying of it, but by now, it is clear that being male is also a factor. Data and studies from different countries across the globe involving China, the United States of America, and European nations such as Italy have showed that although there is no difference based on sex in the number of cases testing positive for the virus, more men died from the virus, and the case-fatality ratio is greater among men than women. Women are infected by the virus as frequently as men but men are more likely to contract severe forms of disease and succumb to it. The reason behind this sex-biased mortality seen in Covid-19 cannot be explained by a single genetic or social factor. The present short communication aims at enumerating the possible reasons behind this gender-biased pandemic.

Role of Cytokeratin-7 in the pathogenesis of odontogenic cysts - an immunohistochemical study.

INTRODUCTION: Odontogenic cysts are distinct entities and quite a common occurrence in the jaw bones. These are individual lesions which arise from the same odontogenic apparatus but with varying pathogenesis. Cytokeratins are integral components in tooth development and are expressed across the odontogenic tissues in physiological and pathological states. AIM: To elucidate the role of cytokeratin-7 in the pathogenesis of odontogenic cysts by immunohistochemistry. METHOD: Cytokeratin-7 (CK-7) was assessed in 39 cases of odontogenic lesions retrieved from the archival files which included 15 cases of dentigerous cysts (DC), 12 cases of odontogenic keratocysts (OKC) and 12 cases of radicular cysts (RC) and also 8 cases of control specimens. STATISTICAL ANALYSIS: Results obtained were statistically analyzed using chi-square test to assess the association between different odontogenic cysts used in this study and Cytokeration-7 staining. The difference was considered to be of statistical significance if the p value was ≤ 0.05. RESULTS: CK7 expression was maximum in dentigerous cycts (66.66%) followed by radicular cysts (41.66%) and odontogenic keratocysts (16.6%). On evaluation of staining and expression pattern, highest positivity is shown in dentigerous cysts and the positivity is seen in suprabasal (60%) and superficial layers (40%) whereas radicular cysts and odontogenic keratocysts showed positivity in superficial and spinous layers. CONCLUSION: Cytokeratin-7 expression correlates with the degree of differentiation of the epithelium. So the cysts with a well-differentiated epithelium (RC and DC) express CK-7, while the cysts with a less well-differentiated epithelium (OKC) show slight positivity. Thus it can be useful to differentiate OKC from DC and RC.

Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites.

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, (+)-α-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 [3H]-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 (Ki = 1.0-2.8 nM), rat forebrain (Ki = 4.2 nM), and human platelets (Ki = 2.6-3.3 nM). Valbenazine (Ki = 110-190 nM) and NBI-136110 (Ki = 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-HT1A, 5-HT2A, 5-HT2B) or dopamine (D1 or D2) 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)].

Comparative Evaluation of the Effect of Menstruation, Pregnancy and Menopause on Salivary Flow Rate, pH and Gustatory Function.

OBJECTIVE: There are five situations in a women's life during which hormone fluctuations make them more susceptible to oral health problems - during puberty, at certain points in the monthly menstrual cycle, when using birth control pills, during pregnancy, and at menopause. The present study aimed at evaluating the effect of menstruation, pregnancy and menopause on salivary flow rate, pH and gustatory function. MATERIALS AND METHODS: The study was carried out on 120 patients including 30 controls (with normal menstrual cycle of 28 to 30 d) and 90 cases (30 patients within three days of menstruation, 30 pregnant and 30 postmenopausal). Paraffin-stimulated saliva samples were obtained by expectoration to calculate salivary flow rate, pH was measured electrometically and patients were prospectively evaluated for gustatory function. Then, whole mouth taste test was performed in which the quality identification and intensity ratings of taste solutions were measured. RESULTS: No statistically significant difference was found between the groups with respect to salivary flow rate but pH values were significantly lower in post menopausal women (p<0.05). Regarding correct quality identification the results were non-significant. Intensity for taste perception for sucrose was significantly lower in postmenopausal women than intensity of taste perception for other tastes (p<0.05). Also, postmenopausal women reported change in their dietary habits as all of them expressed liking for sweeter food. CONCLUSION: Reduced salivary flow rate and pH in postmen-opausal women may make them more prone to the occurrence of oral health problems. Also, pregnant and postmenopausal women appeared to have a reduced perception of sucrose, which can alter eating habits, such as intake of more sweet foods whereas no significant difference is observed in taste perception of NaCl, citric acid and quinine hydrochloride between the subjects.

Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H1-antihistamines for insomnia.

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6.

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.

Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.

Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.

Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia.

A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.

Novel benzothiophene H1-antihistamines for the treatment of insomnia.

SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.

The discovery and structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia.

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.

Validation and application of a liquid chromatography-tandem mass spectrometric method for the simultaneous determination of testosterone and dihydrotestosterone in rat prostatic tissue using a 96-well format.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to extract and quantify the androgen concentration in the rat prostate. This method introduced a novel 96-well plate format for the extraction and derivatization of testosterone (T) and dihydrotestosterone (DHT) from rat prostatic tissue that greatly simplified the sample preparation procedure. Due to the difficulty to obtain reproducible specimens with non-detectable level of androgen, a matrix-free standard solution was used for method validation. Both T and DHT calibration curves were linear over the calibration range (12.5-2500 pg) with correlation coefficient values greater than 0.9900. The intra-day and inter-day accuracy, reported as %bias, and precision, reported as %CV, of T and DHT were within +/-10%. The lower limit of detection (LLOD) and lower limits of quantification (LLOQ) for both T and DHT were determined to be 5 and 12.5 pg. The validation results demonstrated the selectivity, sensitivity, accuracy, precision, linearity and ruggedness of the method, as well as the suitability of the method for simultaneous detection of T and DHT in rat prostatic tissues. The validated method was successfully applied to determine the physiological T and DHT level in rat prostatic tissues. Similarly to the serum concentration profile pattern, T and DHT intraprostatic levels peaked 2 h after lights-on and decreased after lights-off with DHT level approximately 4-fold greater than T.

Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia.

Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

A pharmacokinetic evaluation of five H(1) antagonists after an oral and intravenous microdose to human subjects.

AIMS: To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS: Five H(1) 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. RESULTS: The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), 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. CONCLUSIONS: Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.

N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy.

In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.

Discovery of sodium 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}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.

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.

Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties.

A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.