In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia.

PURPOSE: Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103. METHODS: Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront. RESULTS: Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species. CONCLUSIONS: Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia.

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure-activity relationships.

Usefulness of prenatal magnetic resonance imaging in differential diagnosis of fetal congenital cystic adenomatoid malformation and bronchopulmonary sequestration.

BACKGROUND: Congenital cystic adenomatoid malformation (CCAM) and bronchopulmonary sequestration (BPS) are the most common lung diseases in fetuses. There are differences in the prognosis and treatment of CCAM and BPS, and the clinical diagnosis and treatment plan is usually prepared prior to birth. Therefore, it is quite necessary to make a clear diagnosis before delivery. CCAM and BPS have similar imaging features, and the differentiation mainly relies on the difference in supply vessels. However, it is hard to distinguish them due to invisible supplying vessels on some images. AIM: To explore the application value of magnetic resonance imaging (MRI) in the differential diagnosis of fetal CCAM and BPS. METHODS: Data analysis for 32 fetuses with CCAM and 14 with BPS diagnosed by prenatal MRI at Huzhou Maternal and Child Health Care Hospital and Anhui Provincial Children's Hospital from January 2017 to January 2020 was performed to observe the source blood vessels of lesions and their direction. Pathological confirmation was completed through CT examination and/or operations after birth. RESULTS: After birth, 31 cases after birth were confirmed to be CCAM, and 15 were confirmed to be BPS. The CCAM group consisted of 21 macrocystic cases and 10 microcystic cases. In 18 cases, blood vessels were visible in lesions. Blood supply of the pulmonary artery could be traced in eight cases, and in 10 cases, only vessels running from the midline to the lateral down direction were observed. No lesions were found in four macrocystic cases and one microcystic case with CCAM through CT after birth; two were misdiagnosed by MRI, and three were misdiagnosed by prenatal ultrasonography. The BPS group consisted of 12 intralobar cases and three extralobar cases. Blood vessels were visible in lesions of nine cases, in four of which, the systemic circulation blood supply could be traced, and in five of which, only vessels running from the midline to the lateral up direction were observed. Three were misdiagnosed by MRI, and four were misdiagnosed by prenatal ultrasonography. CONCLUSION: CCAM and BPS can be clearly diagnosed based on the origin of blood vessels, and correct diagnosis can be made according to the difference in the direction of the blood vessels, but it is hard distinguish microcystic CCAM and BPS without supplying vessels. In some CCAM cases, mainly the macrocystic ones, the lesions may disappear after birth.

Analysis of magnetic resonance imaging features of ovarian thecoma.

To investigate the magnetic resonance imaging (MRI) findings in ovarian thecoma and improve preoperative diagnostic accuracy.Retrospective analysis was performed on 45 patients with surgically and pathologically confirmed ovarian thecoma. Patients were grouped into those with maximum lesion diameter ≥5 cm and <5 cm. Diagnostic scores (up to 6 points) were evaluated on the basis of MRI performance.The ≥5 cm group contained 36 cases (cystic necrosis, 32 cases) with the following findings: T1WI: isointense signal, 22 cases; slightly hypointense signal, 14 cases; T2WI: isointense signal, 6 cases; slightly hypointense signal, 21 cases; slightly hyperintense signal, 9 cases; Diffusion-weighted imaging (DWI): hyperintense signal, 23 cases; mixed hyperintense signal, 13 cases; slight enhancement on dynamic enhanced scans; pelvic fluid accumulation, 31 cases. The diagnostic score evaluations yielded 6 points in 31 cases, 5 points in 1 case, 4 points in 2 cases, and 3 points in 2 cases. The <5 cm group contained 9 cases (cystic necrosis, 3 cases) with the following findings: T1WI: isointense signal, 3 cases; slightly hypointense signal, 6 cases; T2WI: isointense signal, 2 cases; slightly hypointense signal, 4 cases; slightly hyperintense signal, 3 cases; DWI, hyperintense signal; slight enhancement in 8 cases and significant enhancement in 1 case; pelvic fluid accumulation, 4 cases. The diagnostic score evaluations yielded 6 points in 3 cases, 5 points in 1 case, 4 points in 4 cases, and 3 points in 1 case. (iii) Incidence of pelvic fluid accumulation and cystic necrosis differed depending on the size of the lesion (P = .007, .000).Larger lesions show hyperintense or mixed hyperintense signals on DWI along with pelvic fluid and cystic necrosis; whereas, smaller lesions show a hyperintense signal on DWI, cystic necrosis is rare. MRI characteristics along with the patient age and laboratory findings can improve the accuracy of preoperative diagnosis of these lesions.

Benzotriazole-Assisted Aromatic Ring Annulation: Efficient and General Syntheses of Polysubstituted Naphthalenes and Phenanthrenes.

(Benzotriazol-1-ylmethyl)benzenes and -naphthalenes 1a-f, easily accessible from benzyl bromides and benzotriazole, readily undergo lithiation and subsequent 1,4-addition to alpha,beta-unsaturated aldehydes and ketones. Intramolecular cyclization of the products, induced by acetic acid-hydrobromic acid or polyphosphoric acid (PPA), followed by simultaneous dehydration and debenzotriazolylation furnishes a wide range of polysubstituted naphthalenes 7a-f and of phenanthrenes 9 and 11 in moderate to good yields in one-pot procedures. If compounds 1 are first lithiated and reacted with electrophiles, the resulting alkylation products undergo similar annulation reactions with alpha,beta-unsaturated carbonyl compounds to provide the more highly substituted naphthalenes 6a,b and phenanthrenes 10a,b in moderate overall yields.

Novel and Efficient Insertions of Carbons Carrying O-, S-, and N-Linked Substituents: Synthesis of alpha-Alkoxyalkyl, alpha-(Alkylthio)alkyl, and alpha-(Carbazol-9-yl)alkyl Ketones.

A wide variety of benzotriazolyl-stabilized anions 2, obtained by the lithiation of 1-(alpha-alkoxyalkyl)-, 1-[alpha-(alkylthio)alkyl]-, and 1-[alpha-(carbazol-9-yl)alkyl]benzotriazoles 1, on reaction with aliphatic and aromatic aldehydes and ketones, followed by rearrangement induced by heating in the presence of zinc bromide, furnish one-carbon-homologated alpha-alkoxyalkyl, alpha-(alkylthio)alkyl, and alpha-(carbazol-9-yl)alkyl ketones 4 in simple one-pot operations in good yields with excellent regioselectivity. In several alkoxymethylene insertions, intermediate 2-alkoxyoxiranes were separated in good yields, demonstrating the epoxide mechanism for the rearrangements and providing a facile approach to polysubstituted 2-alkoxyoxiranes, another class of important compounds.

Efficient Syntheses of Substituted Carbazoles and Cyclopent[b]indoles from 1-Methyl-3-(benzotriazol-1-ylmethyl)indole.

1-Methyl-3-(benzotriazol-1-ylmethyl)indole (1) undergoes lithiation and 1,4-addition with a variety of alpha,beta-unsaturated ketones and aldehydes. Subsequent treatment with an acidic resin in refluxing 1,4-dioxane causes intramolecular cyclization followed by aromatization to furnish a wide range of 1,3-di-, 2,3-di-, and 1,2,3-trisubstituted carbazoles 6a-j and 8 in moderate to excellent yields. NMR study is described to discriminate between structures of types 6 and 8 on the basis of (1)H-(13)C long-range correlation. Treatment of 1 with styrenes in the presence of zinc bromide results in formal [3 + 2] cycloaddition to give cyclopent[b]indoles 14a-c in good yields. When 1 is first lithiated and reacts with electrophiles, the resulting alkylation products undergo similar [3 + 2] additions with styrenes to give 1-functionalized cyclopent[b]indoles 15 and 16with a high degree of stereoselectivity.

General and Efficient Insertions of Carbons Carrying Aryl and Heteroaryl Groups: Synthesis of alpha-Aryl- and alpha-Heteroaryl-Substituted Ketones.

Anions formed from the lithiation of a variety of 1-(arylmethyl)- and 1-(heteroarylmethyl)benzotriazoles 1 with n-BuLi underwent addition to aliphatic and aromatic aldehydes and cyclic and acyclic ketones. Subsequent in situ thermal rearrangements of the intermediates in the presence of zinc bromide provided one-carbon chain-extended or ring-expanded alpha-aryl- and alpha-heteroaryl-substituted ketones 2 in moderate to excellent yields in simple one-pot operations with excellent regioselectivity in most cases. Substituent effects on the relative migration rates were investigated in the insertion reactions of 1-(4-methoxybenzyl)benzotriazole (1e) with XC(6)H(4)COPh. The small and negative Hammett rho(+) value (-0.92) suggested that the rearrangements proceed via early, reagent-like, electron deficient transition states.

Benzotriazole-Mediated [2,3]-Wittig Rearrangement. General and Stereocontrolled Syntheses of Homoallyl Alcohols and beta,gamma-Unsaturated Ketones.

Readily accessible allyl 1-(benzotriazol-1-yl)alkyl ethers (13 and 19), upon treatment with 2.5 equiv of nucleophilic lithium reagents, give secondary and tertiary homoallyl alcohols (16 and 21), respectively, exclusively in the E configuration in excellent yields. This is achieved by deprotonation followed by [2,3]-Wittig rearrangement, departure of the benzotriazolyl group, and then nucleophilic addition to the resulting carbonyl compound. Following a similar protocol, primary E-homoallyl alcohols 18 are prepared in good yield by the reaction of ethers 13 with LDA in the presence of NaBH(4). Our approach complements the stereochemical Z-selective syntheses of primary homoallyl alcohols of Still and of Bruckner. Wittig rearrangement of the anions of 19 generated with LDA analogously furnishes E-beta,gamma-unsaturated ketones 20 in excellent yields.