Ish Kumar Khanna

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Part 2 ☆

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Buprenorphine - an attractive opioid with underutilized potential in treatment of chronic pain.

Despite proven clinical utility, buprenorphine has not been used widely for the treatment of chronic pain. Questions about “ceiling effect” or bell-shaped curve observed for analgesia in preclinical studies and potential withdrawal issues on combining with marketed μ-agonists continue to hinder progress in expanding full potential of buprenorphine in the treatment of cancer and noncancer pain. Mounting evidence from clinical studies and conclusions drawn by a panel of experts strongly support superior safety and efficacy profile of buprenorphine vs marketed opioids. No ceiling on analgesic effect has been reported in clinical studies. The receptor pharmacology and pharmacokinetics profile of buprenorphine is complex but unique and contributes to its distinct safety and efficacy. The buprenorphine pharmacology also allows it to be combined with other μ-receptor opioids for additivity in efficacy. Transdermal delivery products of buprenorphine have been preferred choices for the management of pain but new delivery options are under investigation for the treatment of both opioid dependence and chronic pain.

Fatty acid amide hydrolase inhibitors--progress and potential.

Fatty acid amide hydrolase (FAAH) is responsible for hydrolysis of endocannabinoid, anandamide (AEA), and N-acyl ethanolamines such as palmitoylethanolamine (PEA) and N-oleoylethanolamide (OEA). Genetic deletion or pharmacological inactivation of FAAH shows site-specific elevation of AEA that plays a role in the modulation of pain and other neurodegenerative disorders. The review elaborates recent progress and current status of diverse structural classes of reversible and irreversible FAAH inhibitors. The discussion also addresses ligand-enzyme active site interactions and mechanism of enzyme inactivation, emerging approaches to novel FAAH inhibitors, and ongoing efforts to address gaps in therapeutic utility of FAAH inhibitors.

Targeting Soluble Epoxide Hydrolase for Inflammation and Pain - An Overview of Pharmacology and the Inhibitors

Chronic inflammation is an important contributing factor to a variety of human diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and atherosclerosis. Epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation yields epoxyeicosatrienoic acids (EETs). EETs have a variety of biological effects including modulation of inflammation, vascular smooth muscle migration and platelet aggregation. The EETs levels are regulated by soluble epoxide hydrolase (sEH), the major enzyme responsible for their degradation and conversion to inactive dihydroxyeicosatrienoic acids (DHETs); thereby limiting many of the biological actions of EETs. The molecular and pharmacological inhibition of sEH has been studied extensively for benefits on the cardiovascular system. More recent studies suggest the importance of EETs and sEH in pain and inflammation. This review will discuss the current status and emerging evidence on the role of sEH and sEH inhibitors in chronic inflammatory conditions such as atherosclerosis, colitis and arthritis. Although steroids and non-steroidal anti-inflammatory drugs are effective, their chronic use is limited by the metabolic and cardiovascular side effects. Currently there are no small molecule drugs for treatment of chronic inflammation and associated pain and sEH inhibitors with their intrinsic cardiovascular protective effects can potentially fill this void.

Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

Synthesis and SAR studies of benzimidazole derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Focus to detune hERG inhibition

Melanin concentrating hormone receptor 1 (MCHR1) antagonists are potentially useful in the treatment of several CNS disorders such as obesity, stress, depression and anxiety. In a previous article, we have described a novel series of benzimidazoles as MCHR1 antagonists. These compounds showed good efficacy in obesity models but the lead compound also showed potent inhibition of hERG potassium channel. Described herein the medicinal chemistry attempts to reduce hERG inhibition while retaining MCHR1 antagonistic profile.

A multimodal disease modifying approach to treat neuropathic pain--inhibition of soluble epoxide hydrolase (sEH).

Both neuronal and non-neuronal mechanisms have been proposed to contribute to neuropathic pain (NP). All currently approved treatments for NP modulate neuronal targets and provide only symptomatic relief. Here we review evidence that inhibition of soluble epoxide hydrolase (sEH), the enzyme that degrades epoxyeicosatrienoic acids (EETs), has potential to be a multimodal, disease modifying approach to treat NP: (1) EET actions involve both endogenous opioid system and the GABAergic systems thus provide superior pain relief compared to morphine or gabapentin, (2) EETs are directly anti-inflammatory and inhibit expression of inflammatory cytokines and adhesion molecules thus can prevent continued nerve damage; and (3) EETs promote nerve regeneration in cultured neurons. Thus, an sEH inhibitor will not only provide effective pain relief, but would also block further nerve damage and promote healing.

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

Chapter 12 Recent Trends in HDL Modulating Therapies

Publisher Summary High-density lipoprotein (HDL) is an important and attractive target to reduce atherosclerotic progression or induce its regression. Despite a large body of evidence supporting the atheroprotective benefits of HDL, drugs available on the market that raise HDL are limited. Amongst the marketed drugs, the statins offer only marginal increases (5–10%), while fibrates elevate HDL levels by 10–15%. Fibrates, such as fenofibrate, gemfibrozil, bezafibrate, clofibrate, and ciprofibrate moderately enhance HDL levels by 10–15%. Fibrates are weak activators of peroxisome proliferator-activated receptor alpha (PPARα) and decrease triglycerides (TG) levels and increase HDL. Different mechanisms have been proposed by which fibrates elevate plasma HDL levels. Induction of PPARα in the liver leads to increased synthesis of apoA-I, resulting in enhancement of new HDL particles. Niacin is the most potent HDL-raising drug (20–30%) on the market, and also provides some reduction in TG and low-density lipoprotein cholesterol (LDL-C) levels. Clinical studies with niacin as monotherapy or in combination with statins have yielded marked reductions in cardiovascular events and enhanced angiographic plaque regression. Niacins utility has, however, been limited by its adverse effects, in particular cutaneous vasodilation and hepatotoxicity. Emerging clinical compounds such as Cholesteryl ester transfer protein (CETP) inhibitors that mediate the transfer of CE from HDL to LDL and very low-density lipoprotein (VLDL), and of TGs from VLDL to LDL and HDL are also discussed.