Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor

Two new series of EP₄ antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP₄ receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.     

Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO₂ permeability was also excellent for compound 18 .     

Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K

The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.     

Synthesis and vasorelaxant activity of new coumarin and furocoumarin derivatives

We have synthesized a new series of coumarins and furocoumarins and evaluated their vasorelaxant activity in rat aorta rings pre-contracted with noradrenaline or by depolarisation with high KCl. The new furocoumarins relax smooth vascular muscle with a profile similar to that of khellin (a furochromone that directly relaxes smooth muscle) and at a greater potency, suggesting that these compounds have a potential interest for the development of new and more efficient vasodilator drugs.     

Synthesis and SAR of substituted tetrahydrocarbazole derivatives as new NPY-1 antagonists

The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.     

Structure based evolution of a novel series of positive modulators of the AMPA receptor

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.     

Synthesis and antidepressant-like action of stereoisomers of imidobenzenesulfonylaziridines in mice evaluated in the forced swimming test

The present study describes the chemical synthesis and pharmacological evaluation of a new series of eleven compounds stereoisomers of imidobenzenesulfonylaziridines in the forced-swimming test (FST) in mice. The pharmacological results of these compounds show that six of them, given intraperitoneally, reduced the immobility time of mice evaluated in the FST, an antidepressant-like profile of action similar to imipramine, a well-known standard antidepressant drug used for comparison, without compromising the animals' motor performance. The putative antidepressant-like action demonstrated here indicates their viability for the development of new therapeutic options for the treatment of depression.     

Discovery of the potent non-steroidal glucocorticoid receptor modulator BAY 1003803 as clinical candidate

We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure, considerations were made as to how physicochemical properties and safety concerns relate to structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with a pharmacokinetic profile suitable for topical application.     

Aza-retinoids as novel retinoid X receptor-specific agonists

A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.     

The design of 8,8-dimethyl[1,6]naphthyridines as potential anticonvulsant agents

Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.     

Piperidinyl-2-phenethylamino inhibitors of DPP-IV for the treatment of Type 2 diabetes

A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.     

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, Log D, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.     

A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation

A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.     

Design and synthesis of a novel series of cyanoindole derivatives as potent γ-secretase modulators

The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.     

Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues

In this work we reported the synthesis and the trypanocidal profile of new 1,3,4-thiadiazole-2-arylhydrazone derivatives of nitroimidazole series (4) or phenyl series (5), designed by exploring the molecular hybridization approach between megazol (2) and guanyl hydrazone derivative (3). The evaluation of the activity against bloodstream trypomastigote forms of Trypanosoma cruzi forms lead us to identify a new potent trypamomicide prototype, that is, brazilizone A (4k), which present an IC₅₀/24 h = 5.3 μM.     

Fourier harmonic analysis of the sagittal profile of the Plesianthropus transvaalensis (STS5) skull

An analytical morphometrical investigation of fronto facial profile of Plesianthropus transvaalensis was carried out by means of Fourier spectral series. Amplitude of contributors was evaluated in comparison with harmonic sets of a modern skull and two "mosaics" obtained by a convenient merging of segments of modern and hominid skull profiles. Patterns are distinctly different in Plesianthropus and modern profile because amplitude of second harmonic is greater than first in the former and viceversa in the latter; moreover while in Plesianthropus first and second harmonic give the same phase, it does not occur for modern skull. Fourier series of "mosaic" obtained by frontal profile of Plesianthropus and facial profile of modern resembles the set of modern skull while "mosaic" of modern frontal profile and hominid facial one resembles closely pattern of Plesianthropus.     

Tetrahydrocarboline analogs as MCH-1 antagonists

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.     

Natural and synthetic 2′-hydroxy-chalcones and aurones: Synthesis,characterization and evaluation of the antioxidant and soybean lipoxygenase inhibitory activity

A series of 2′-hydroxy-chalcones and their oxidative cyclization products, aurones, have been synthesized and tested for their antioxidant and lipoxygenase inhibitory activity. The natural product aureusidin (31) was synthesized in high yield by a new approach. An extensive structure-relationship study was performed and revealed that several chalcones and aurones possess an appealing pharmacological profile combining high antioxidant and lipid peroxidation activity with potent soybean LOX inhibition.     

Potent, selective MCH-1 receptor antagonists

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.     

Design and synthesis of novel potent antinociceptive agents: methyl-imidazolyl N-acylhydrazone derivatives

This paper describes recent results of design, synthesis and pharmacological evaluation of new N-heterocyclic functionalized N-acylhydrazone compounds, belonging to the 2-methyl-imidazolyl-3-acylhydrazone class (4a-e). These compounds were planned by applying the molecular simplification strategy to propose the structural modifications on the previously described functionalized imidazo [1,2-a]pyridine 3-acylhydrazone series (2), which presented an important analgesic profile. This new series (4) was synthesized in order to investigate the possible pharmacophoric contribution of the N-heteroaromatic ring and N-acylhydrazone moieties to the analgesic activity. Compounds 4a-b are the most potent antinociceptive agents from this series.