Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT Receptor Agonists.

Agonism of the 5-HT receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT and 5-HT receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.

Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119.

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes.

Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists.

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.

Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT(2C) receptor agonists.

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy.

Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists.

A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.

Characterization of a novel and selective CB1 antagonist as a radioligand for receptor occupancy studies.

Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data.

Discovery and development of 5-HT(₂C) receptor agonists for obesity: is there light at the end of the tunnel?

Ever since the observation of late-onset obesity during the phenotypic characterization of the 5-HT(₂C) knock-out mouse, the serotonin 5-HT(₂C) receptor has been a drug target for obesity. Small-molecule agonists have repeatedly been shown to reduce food intake and body weight in rodent models of obesity. To date, however, only one compound, lorcaserin, has completed Phase III trials and currently awaits an US FDA decision following a negative advisory committee meeting.

Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.

Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described.

Position 5.46 of the serotonin 5-HT2A receptor contributes to a species-dependent variation for the 5-HT2C agonist (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: impact on selectivity and toxicological evaluation.

Successful development of 5-HT(2C) agonists requires selectivity versus the highly homologous 5-HT(2A) receptor, because agonism at this receptor can result in significant adverse events. (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (compound 1) is a potent 5-HT(2C) agonist exhibiting selectivity over the human 5-HT(2A) receptor. Evaluation of the compound at the rat 5-HT(2A) receptor, however, revealed potent binding and agonist functional activity.

Agonists of the serotonin 5-HT2C receptor: preclinical and clinical progression in multiple diseases.

The serotonin 5-HT2C receptor is a G-protein-coupled receptor and is one of the 14 subtypes that constitutes the serotonin receptor family. Agonists of 5-HT2C have been implicated as potential treatments for diseases of significant unmet medical need, including obesity and schizophrenia. Despite approximately 10 years of discovery efforts, 5-HT2C agonists have only recently advanced into the clinic, likely because many of the early drug discovery efforts experienced significant difficulties with attaining receptor selectivity.

Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A.

Functional selectivity and classical concepts of quantitative pharmacology.

The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor.

Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity.

Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine.

Central G-Protein Coupled Receptors (GPCR)s as molecular targets for the treatment of obesity: assets, liabilities and development status.

In the last decade, the G-Protein-Coupled Receptor (GPCR) superfamily has emerged as a very promising and enriched source of therapeutic targets for the treatment of obesity. GPCRs represent the largest family of mammalian proteins, with approximately 1000 members. It is estimated that the GPCR family may comprise greater than 1% of the human genome and is the molecular target for approximately 30% of currently marketed drugs.

N-phenylphenylglycines as novel corticotropin releasing factor receptor antagonists.

Screening of a computationally designed synthetic library led to the discovery of the N-phenylphenylglycines (NPPGs) as a novel class of human corticotropin releasing factor (h-CRF(1)) antagonists. Several NPPGs with greater potency than the original hit 1 were rapidly identified, and resolution of the racemate demonstrated that only the R-enantiomer displays activity. This structural class represents the first example of a non-peptide CRF(1) antagonist with a stereochemically distinct receptor binding affinity.

Novel, highly potent, selective 5-HT2A/D2 receptor antagonists as potential atypical antipsychotics.

The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT(2A), 5-HT(2C) and D(2) receptors, and in vivo efficacy as 5-HT(2A) antagonists is described. The structure-activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT(2A)/D(2) receptor dual antagonists as potential atypical antipsychotics.