Eric A. Voight

Transient receptor potential vanilloid-1 antagonists: a survey of recent patent literature

Importance of the field: Transient receptor potential vanilloid-1 (TRPV1, vanilloid receptor-1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and by capsaicin, the active ingredient in chili peppers. TRPV1 is expressed predominantly on sensory neurons where it is proposed to serve as a key nodal point in pain transmission pathways. Pharmacological blockade of TRPV1 represents a compelling strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management. Area covered in the review: This review summarizes patent literature and progress in defining the utility of small molecule TRPV1 antagonists during 2008 – 2009. What the reader will gain: Representative compounds and key characterization data comprising multiple chemical series are highlighted. Take home message: The continued profusion of reports, in both the primary and patent literature, attests to the sustained interest in the TRPV1 class of therapeutics. Although a number of compounds have now been brought forward for human clinical trials, the therapeutic utility of TRPV1 antagonists is yet to be validated unequivocally.

Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis.

The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by etherification and an alkene cross metathesis with an unsaturated alpha-phenylselenyl ester en route to completing the total synthesis.

Target-Directed Synthesis of Antibacterial Drug Candidate GSK966587

An efficient enantioselective total synthesis of the potent antibiotic GSK966587 was accomplished. Highlights of the synthesis include two innovative Heck reactions, a highly selective zincate base directed ortho-metalation, Sharpless asymmetric epoxidation, and a fully convergent final step fragment coupling.

Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.

Formal synthesis of (−)-N-acetylneuraminic acid (Neu5Ac) via desymmetrization by ring-closing metathesis

Abstract A formal total synthesis of (−)- N -acetylneuraminic acid (Neu5Ac), the most naturally abundant sialic acid, has been accomplished using a rigid 6,8-dioxabicyclo[3.2.1]octane template for stereoselective introduction of all oxygen and nitrogen functionality. The template was obtained via a novel ketalization/ring-closing metathesis bond construction strategy, taking advantage of an advanced intermediate in our KDN synthesis to complete the efficient assembly of Neu5Ac.

Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats

Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5′-I-RTX.

Synthesis of Oxazolo[4,5-c]quinoline TRPV1 Antagonists

An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel.

Synthesis of Substituted Cyclopropanecarboxylates via Room Temperature Palladium-Catalyzed α-Arylation of Reformatsky Reagents

The room temperature palladium-catalyzed cross-coupling of aromatic and heteroaromatic halides with Reformatsky reagents derived from 1-bromocyclopropanecarboxylates provides an exceptionally mild method for enolate α-arylation. The method is tolerant of a wide range of functionalities and dramatically shortens many of the existing routes to access widely used 1,1-disubstituted cyclopropanecarboxylate derivatives.