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Objective: Some individuals with attention-deficit/hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. This study examined whether solriamfetol could have a favorable pattern of effects and tolerability as a treatment for ADHD in adults., Methods: Sixty adults with DSM-5 ADHD participated from August 2021 through January 2023 in a remotely conducted, randomized, double-blind, placebo-controlled, 6-week dose-optimization trial of 75 mg or 150 mg of solriamfetol. Measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), which was our primary outcome measure, as well as the Clinical Global Impressions scale (CGI), vital signs, the Global Assessment of Functioning (GAF), the Behavior Rating Inventory of Executive Function-Adult Form (BRIEF-A), the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and a modified Adult ADHD Self-Report Scale (MASRS)., Results: Solriamfetol was well tolerated, with no significant effect on mean heart rate (+3.7 vs +2.2 bpm, P  = .5609), systolic blood pressure (+2.4 vs +1.5 mm Hg, P  = .6474), or diastolic blood pressure (+1.1 vs +1.5 mm Hg, P  = .8117). There was no statistically significant treatment effect on occurrence of adverse events. Compared to individuals on placebo, individuals on solriamfetol treatment experienced adverse events at a rate of at least 10 percentage points higher in the categories of decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic. Compared to individuals on placebo, by study endpoint, a greater proportion of individuals in the treatment group met the a priori-defined treatment response (CGI score indicating much or very much improved and AISRS score reduced ≥ 25%: 45% vs 6.9%, P  = .0020); those treated with solriamfetol also had greater improvement in total AISRS scores by week 3 through week 6 ( P  = .0012; week 6 effect size = 1.09). Significantly more solriamfetol-treated adults than placebo-treated adults had 0.5-standard deviation improvement in T-score on the BRIEF-A Global Executive Composite ( P  = .0173); those treated with solriamfetol also had greater mean change in GAF score (-4.8 vs -0.3, P  = .0006) and greater mean MASRS total score change ( P  = .0047; effect size = 1.23). Mean ESS score improved more with solriamfetol than with placebo ( P  = .0056), but this difference did not predict AISRS response ( P  = .3735). There was no significant association between solriamfetol and change in PSQI scores., Conclusions: Solriamfetol may be a novel and effective treatment for the management of ADHD in adults. Further replication in larger trials is indicated., Trial Registration: ClinicalTrials.gov identifier: NCT04839562., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26 , a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

Clinical development of drugs for CNS disorders can be a challenging and risky endeavor. In this article we look at the steps required to move a preclinical candidate compound into clinical development. We use the case study of ALB-127158(a), an MCH1 antagonist for the treatment of obesity via a central mechanism to highlight the steps needed to move into early clinical development. Preclinical studies demonstrated that the compound produced significant weight loss in rodents. Based on the observation that the weight loss was caused by a reduction in food intake it was possible to build measures of ingestive behavior into the early clinical development plan. Single and multiple ascending dose studies were conducted in normal and overweight volunteers. The compound was safe and well tolerated with good PK characteristics. ALB-127158(a) was shown to have some effects on measures of 'hunger' and 'desire to eat', unfortunately these effects only occurred at doses higher than those predicted from the preclinical studies. A subsequent study looking at compound levels in the cerebrospinal fluid (CSF) suggested lower brain exposure than seen in the preclinical models. Based on this data and the limited efficacy observed it was possible to terminate further progression of this compound for obesity before costly long-term weight loss studies were initiated. However, recent reports have demonstrated that MCH acting via MCH1 receptors located on intestinal epithelial cells may be a critical mediator of inflammatory responses within the gastrointestinal (GI) tract. MCH1 receptor antagonists may therefore have a beneficial effect in disorders such as inflammatory bowel disease (IBD). Based on this evidence a peripherally selective MCH1 receptor antagonist such as ALB-127158(a) may be a potential treatment for IBD. This example demonstrates how using data from the preclinical studies is possible to build decision points into an early clinical development plan that will allow early assessment of potential efficacy and allow timely go/no go decisions., (© 2013.)

A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines. These novel series incorporate additional H-bonding functions and can be more water soluble than their naphthyridinone progenitors; diazepine 16c is shown to be efficacious in a mouse infection model.

Versatile intermediates 12'-iodovinblastine, 12'-iodovincristine and 11'-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model.

Acylnitroso Diels-Alder cycloadduct (11, 37, and 45)- and cyclopentenyl acetate (8 and 9)-derived allylindium(III) species were generated in situ from palladium(0) catalysts and indium(I) iodide, and the stereo- and regiochemistry of their additions to aldehydes and ketones were investigated. Solvent, catalyst, and ionic effects were examined for the reaction of N-acetyl cycloadduct (11) and benzyloxyacetaldehyde (10). The solvent mixture of THF/H(2)O with Pd(OAc)(2).PPh(3) catalysis was found to be optimal. The addition of N-acetyl cycloadduct to aliphatic aldehydes afforded products in good yields and high regio- and stereoselectivity, with the cis-1,4-isomers constituting 90-95% of the products. The reactions with N-Boc (37a) and N-methylcarbamate (37b) cycloadducts also gave the cis-1,4-products predominantly. The same regio- and stereoselectivity applied to the reactions of 4-acetoxy-1-(N-hydroxyphenyacetamido)cyclopentene (8). 4-Acetoxy-1-phenylacetamidocyclopentene (9), however, afforded trans-1,4-products exclusively. Mechanistic speculations involving chelated transition states are described.

Treatment of acylnitroso hetero Diels-Alder cycloadducts 2 with organomagnesium reagents in the presence of a catalytic amount of copper induces ring opening to afford predominantly monocyclic anti-1,2-hydroxamic acids 12. Alkylmagnesium reagents were found to give superior regio- and stereoselectivities compared with vinyl and arylmagnesium reagents. This cycloadduct ring opening methodology was applied to the synthesis of a unique cyclopentenyl hydroxamic acid-based inhibitor of 5-lipoxygenase.

[reaction: see text] N(4)-Hydroxy-1,4-benzodiazepines were synthesized in a single step from synthetically versatile acylnitroso-derived hetero-Diels-Alder cycloadducts. The efficiency of this transformation was found to be dependent on the NH pK(a) of the cycloadduct sulfonamide.

Treatment of acylnitroso hetero Diels-Alder cycloadducts 2 with iron(III) or copper(II) in an alcohol solvent induces ring opening to afford predominantly monocyclic anti-1,4-hydroxamic acids 3. However, treatment of cycloadducts 2 with copper(II) in toluene reverses the stereoselectivity of the ring opening to afford syn-1,4-hydroxamic acids 4. These regio- and stereoselective processes separately provide anti-1,4- and syn-1,4-disubstituted cyclopentenes while regenerating a hydroxamic acid moiety, thus enhancing the chemical versatility of the Diels-Alder cycloadducts.

[reaction: see text] A conformationally restricted analogue (5) of N(omega)-acetyl-N(omega)-hydroxyornithine and -lysine was synthesized. The synthesis features an efficient acylnitroso hetero-Diels-Alder cycloadduct (1) ring opening with palladium(0) and methylnitroacetate.