Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists.

Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 ß-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.

Highlights on Fluorine-containing Drugs Approved by U.S. FDA in 2023.

Fluorine continues to show its potential applications in drug discovery and development, as reflected by twelve drugs being fluorinated out of the fifty-five approved by the FDA in 2023. This concise review highlights the discovery of each of these fluorine-containing drugs in the past year, including its brand name, date of approval, composition, sponsors, indication, and mechanism of action. The relevant future trend is also briefly discussed.

Orphan GPR52 as an emerging neurotherapeutic target.

GPR52 is a highly conserved, brain-enriched, Gs/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

Highlights on U.S. FDA-approved fluorinated drugs over the past five years (2018-2022).

The objective of this review is to provide an update on the fluorine-containing drugs approved by U.S. Food and Drug Administration in the span of past five years (2018-2022). The agency accepted a total of fifty-eight fluorinated entities to diagnose, mitigate and treat a plethora of diseases. Among them, thirty drugs are for therapy of various types of cancers, twelve for infectious diseases, eleven for CNS disorders, and six for some other diseases. These are categorized and briefly discussed based on their therapeutic areas. In addition, this review gives a glimpse about their trade name, date of approval, active ingredients, company developers, indications, and drug mechanisms. We anticipate that this review may inspire the drug discovery and medicinal chemistry community in both industrial and academic settings to explore the fluorinated molecules leading to the discovery of new drugs in the near future.

An environmentally benign regioselective synthesis of 2-benzyl-4-arylquinoline derivatives using aryl amines, styrene oxides and aryl acetylenes.

A novel and an expedient metal- and solvent-free synthesis of a wide variety of 2-benzyl-4-arylquinoline derivatives is described from readily available aryl amines, styrene oxides and aryl acetylenes in the presence of 10 mol% molecular iodine. This domino reaction occurs under metal- and solvent-free conditions at 120 °C, which avoids the usage of metal catalyst and as a consequence generation of metal waste. The salient features of this methodology are the use of simple starting materials, ease of handling, high regioselectivity, shorter reaction time, atom-economical, step-economical, the formation of one C-N and two C-C bonds and a wide range of functional groups tolerance.

Metal-free synthesis of quinoline-2,4-dicarboxylate derivatives using aryl amines and acetylenedicarboxylates through a pseudo three-component reaction.

An efficient, useful and one-pot protocol for the synthesis of quinoline-2,4-dicarboxylate scaffolds is accomplished from aryl amines and dimethyl/diethyl acetylenedicarboxylates using 20 mol% molecular iodine as a catalyst in acetonitrile at 80 °C. In addition, the mechanistic explanation for the formation of the desired products is disclosed. The pivotal role of molecular iodine in the formation of the major products, diester quinoline derivatives, and the minor product, triesters, in two cases is described in the mechanism. The notable advantages of this method are non-involvement of a metal catalyst, avoiding of metal contamination in the final product as well as waste generation, use of a low cost and eco-friendly catalyst, ease of handling, high regioselectivity, shorter reaction time, the formation of one C-N and two C-C bonds and a broad substrate scope with good yields.

Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline derivatives using aryl amines, aryl aldehydes and styrene oxides.

An efficient and expedient synthetic protocol is reported for the synthesis of 2,3-diarylquinoline derivatives from readily available aryl amines, aryl aldehydes and styrene oxides using 10 mol% copper(ii) triflate by employing three-component reaction. This approach involves the reaction between the in situ generated imine (derived from the aryl amine and aryl aldehyde) and styrene oxide, which enables the formation of the desired products. The present method has several advantages such as high atom-economy, high regioselectivity, easy handling, consecutive one C-N and two C-C bond formation, shorter reaction time and broader substrate scope with good yields.

Newly synthesized 3-sulfenylindole derivatives from 4-hydroxydithiocoumarin using an oxidative cross dehydrogenative coupling reaction (OCDCR): potential lead molecules for antiproliferative activity.

An expedient and efficient synthetic method was developed for the oxidative cross dehydrogenative coupling reaction between 4-hydroxydithiocoumarin and indole at the C-3 position regio-selectively using a combination of 10 mol% molecular iodine and TBHP in the presence of 10 mol% CuBr2 as an additive at room temperature. Mild reaction conditions, good yields and a broad substrate scope are some of the salient features of the present protocol. Additionally, the synthesized 3-sulfenylindoles derived from 4-hydroxydithiocoumarin were converted into biologically active sulfone derivatives. Interestingly, some of the compounds exhibit anti-cell proliferative activity on breast cancer (MCF-7) cells due to reactive oxygen species (ROS) mediated cell damage.

Reaction behaviour of arylamines with nitroalkenes in the presence of bismuth(iii) triflate: an easy access to 2,3-dialkylquinolines.

We report the reaction behaviour of arylamines with nitroalkenes in the presence of bismuth(iii) triflate (10 mol%) and diacetoxyiodobenzene (10 mol%). We obtained 2,3-dialkylquinoline derivatives instead of the expected 3-alkylindole derivatives. The present reaction is an alternative approach for the synthesis of 2,3-dialkylquinoline derivatives under milder conditions. Furthermore, we establish the mechanistic pathway by theoretical calculations using Gaussian 09 software [B3LYP/6-311+G(d,p)], which shows that the conventional aza-Michael reaction is preferred over Michael addition. Aliphatic nitroalkenes behave in a different manner than aromatic nitroalkenes. An aza-Michael adduct gives rise to an imine by the elimination of water which may tautomerize to the corresponding enamine. The resulting imine and enamine intermediates react together to afford the desired quinoline derivatives. This protocol has the advantages of consecutive formation of one C-N and two C-C bonds, high regioselectivity, broad substrate-scope and good yields.

Iodine monobromide catalysed regioselective synthesis of 3-arylquinolines from α-aminoacetophenones and trans-ß-nitrostyrenes.

A simple and efficient method for regioselective synthesis of 3-arylquinolines is described from α-aminoacetophenones and trans-ß-nitrostyrenes using 20 mol% iodine monobromide as a catalyst in acetonitrile solvent at 80 °C. The present method involves tandem reaction of α-aminoacetophenones and trans-ß-nitrostyrenes, formation of two new C-C bonds and cleavage of one C-C bond in a single step. The salient features of the protocol are metal- and oxidant-free reaction conditions, broad substrate scope, and good yields.

Enantiospecific total syntheses of meroterpenoids (-)-F1839-I and (-)-corallidictyals B and D.

Enantiospecific total syntheses of spiromeroterpenoid natural products (-)-F1839-I and (-)-corallidictyals B and D were achieved using the environmentally benign and highly atom economical Lewis acid catalysed Friedel-Crafts reaction and a highly regio- and stereoselective spirocyclic C-O bond formation reaction.