t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template.

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S.

2-Sulfonamidopyridine C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S.

Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists.

A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP)=0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression.

5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K(i(CAP))=0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.

Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor: Structure, Modulators, and Therapeutic Applications.

Transient receptor potential (TRP) channels belong to a superfamily of sensory-related ion channels responding to a wide variety of thermal, mechanical, or chemical stimuli. In an attempt to comprehend the piquancy and pain mechanism of the archetypal vanilloids, transient receptor potential vanilloid (TRPV) 1 was discovered. TRPV1, a well-established member of the TRP family, is implicated in a range of functions including inflammation, painful stimuli sensation, and mechanotransduction. TRPV1 channels are nonselective cation receptors that are gated by a broad array of noxious ligands. Such polymodal-sensor aspect makes the TRPV1 channel extremely versatile and important for its role in sensing burning pain. Besides ligands, TRPV1 signaling can also be modulated by lipids, secondary messengers, protein kinases, cytoskeleton, and several other proteins. Due to its central role in hyperalgesia transduction and inflammatory processes, it is considered as the primary pharmacological pain target. Moreover, understanding the structural and functional intricacies of the channel is indispensable for the therapeutic intervention of TRPV1 in pain and other pathological disorders. In this chapter, we seek to give a mechanistic outlook on the TRPV1 channel. Specifically, we will explore the TRPV1 structure, activation, modulation, ligands, and its therapeutic targeting. However, the major objective of this review is to highlight the fact that TRPV1 channel can be treated as an effective therapeutic target for treating several pain- and nonpain-related physiological and pathological states.

Role of computer-aided drug design in modern drug discovery.

Drug discovery utilizes chemical biology and computational drug design approaches for the efficient identification and optimization of lead compounds. Chemical biology is mostly involved in the elucidation of the biological function of a target and the mechanism of action of a chemical modulator. On the other hand, computer-aided drug design makes use of the structural knowledge of either the target (structure-based) or known ligands with bioactivity (ligand-based) to facilitate the determination of promising candidate drugs. Various virtual screening techniques are now being used by both pharmaceutical companies and academic research groups to reduce the cost and time required for the discovery of a potent drug. Despite the rapid advances in these methods, continuous improvements are critical for future drug discovery tools. Advantages presented by structure-based and ligand-based drug design suggest that their complementary use, as well as their integration with experimental routines, has a powerful impact on rational drug design. In this article, we give an overview of the current computational drug design and their application in integrated rational drug development to aid in the progress of drug discovery research.

Transient receptor potential vanilloid type 1 antagonists: a patent review (2011 - 2014).

INTRODUCTION: Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that can be activated by noxious heat, low pH and vanilloid compounds such as capsaicin. Since TRPV1 acts as an integrator of painful stimuli, TRPV1 antagonists can be used as promising therapeutics for new types of analgesics. AREAS COVERED: This review article covers the patents that claim TRPV1 antagonists and were published during 2011 - 2014. The patent evaluation is organized according to the applicant companies, and the representative chemical entities with important in vitro and in vivo data are summarized. EXPERT OPINION: Many pharmaceutical companies showed promising results in the discovery of potent small molecule TRPV1 antagonists, and recently, a number of small molecule TRPV1 antagonists have been advanced into clinical trials. Unfortunately, several candidate molecules showed critical side effects such as hyperthermia and impaired noxious heat sensation in humans, leading to their withdrawal from clinical trials. Some TRPV1 antagonists patented in recent years (2011 - 2014) overcame these undesirable side effects, making the development of TRPV1 antagonists much more promising.