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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.

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.

We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.

Inhibition of rho kinase (ROCK) has been recognized as an important target for a number of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compound 38. In vitro and in vivo analysis of this compound, including its effects in a monkey model of glaucoma will be discussed.

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.

A Povarov reaction, between an aromatic imine derived from cinnamaldehyde and a cyclic enamide, was employed to rapidly construct the tricyclic core of the alkaloids martinelline and martinellic acid. The cycloaddition was completely regioselective though the exo/endo selectivity was poor. The diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations.

Formal [4+2] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrroloquinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also participated in this chemistry, with the latter favouring formation of the endo -cycloadduct. The cycloadducts derived from methylglyoxalate were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyanoacrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.

Indium trichloride catalysed Diels-Alder reaction of imines derived from anilines with cyclic enamides regioselectively gave the biologically important pyrroloquinoline nucleus, with a cis ring junction, in moderate yield. Although the exo:endo selectivity was in most cases poor, these isomers are readily separated by flash chromatography. The functionality tolerated at both C2 and C7 should allow further elaboration to Martinelline

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels–Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo – endo selectivity was poor. These diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo -isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations.

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.

Enaminones react with itaconic anhydride in methylene chloride at room temperature to give exocyclic enamides as the major products. These can be readily equilibrated to the thermodynamically more stable endocyclic enamides. In substrates where the exocyclic isomer could not be formed only intractable materials were produced from this reaction. An intermediate in this two step process was detected and identified by proton and 13C NMR spectroscopy. In two cases chiral enaminones were employed and the relative stereochemistry at the new chiral centre in the product was established by a crystal structure of compound 27.

Indium trichloride catalysed Diels-Alder reaction of imines derived from anilines with cyclic enamides regioselectively gave the biologically important pyrroloquinoline nucleus, with a cis ring junction, in moderate yield. Although the exo:endo selectivity was in most cases poor, these isomers are readily separated by flash chromatography. The functionality tolerated at both C2 and C7 should allow further elaboration to Martinelline

Methyl 4-acetyl-5-(2-nitrophenyl)pyrrolidine-2-carboxylate 5, readily available in one step by a 1,3-dipolar cycloaddition, undergoes reduction, cyclisation and fragmentation to the corresponding quinoline when treated with hydrogen and palladium.

Formal [4+2] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrroloquinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also participated in this chemistry, with the latter favouring formation of the endo -cycloadduct. The cycloadducts derived from methylglyoxalate were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyanoacrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels–Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo – endo selectivity was poor. These diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo -isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations.

The original structure of a high-throughput screening hit obtained from an external vendor was revised based on multiple NMR studies. The active compound was re-synthesized via a novel route and its structure and biological activity as a BRS-3 agonist were unambiguously confirmed. Multi-gram quantities of the hit were prepared for pharmacokinetic and efficacy studies. The synthetic strategy allowed for the preparation of multiple analogs for SAR exploration.

SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.

This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC50 = 18 nM, hBRS-3) and functional agonist activity (EC50 = 47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.

Methyl 4-acetyl-5-(2-nitrophenyl)pyrrolidine-2-carboxylate 5, readily available in one step by a 1,3-dipolar cycloaddition, undergoes reduction, cyclisation and fragmentation to the corresponding quinoline when treated with hydrogen and palladium.