Rational Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinflammatory Properties

Abstract

A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.

N-Pyridinyl(methyl)-indole-1- or 3-propanamides and propenamides acting as topical and systemic inflammation inhibitors

“…Although the N 1 -4-chlorobenzyl derivatives 32 was less active (72% inhibition), it was found to exhibit a significant selective immunosuppressive effect; it inhibited mouse foot pad swelling in the in vivo delayed type hypersensitivity reaction [17], a response that is mainly linked to the proliferation of the Th1 lymphocytes. Lastly pharmacomodulation aimed at incorporating on indolic nitrogen a morpholinoethyl chain, present notably in CB2 cannabinoid receptor agonists such as WIN-55212-2 [8,9], failed in increasing the activity level of 33 (63% inhibition).…”

“…Recently an indole-1-sulfonyl-3-acetic acid derivative, A [2], was described as a potent and selective CRTH 2 receptor antagonist, inhibiting PGD 2 -induced lymphocyte activation and liable to treat allergic diseases such as atopic dermatitis; reversed amides of indomethacin, such as B, were evaluated as selective COX-2 inhibitors [3] and many of the selective peripheral CB2 receptor agonists [4 -7], currently under study, are cannabimimetic indoles such as WIN-55212-2 [8], possessing potential in alleviating inflammation and pain. Moreover this heterocycle is present in (i) CCR2b…”

Synthesis, Characterization and Evaluation of Analgesic and Anti-inflammatory Activities of Some Novel Indoles

“…Indole ring constitutes an important template for drug design such as the classical NSAIDs indomethacin and indoxole. Furthermore, indole derivatives have been reported to possess promising biological activities including analgesic, anti-inflammatory [2][3][4][5], antihypertensive [6], anticonvulsant [7], antimicrobial [8][9] and selective cyclooxygenase 2 COX 2 inhibitory activities [10][11][12]. Thus, efficient synthesis of novel substituted indole derivative compounds still represent highly pursued objective.…”

Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid, key intermediate in the synthesis of novel 3-amidoindole and indolopyridone cannabinoid ligands

“…3 Further optimization led to a novel cannabinoid ligand 2 which shows high affinity for the CB2 receptor (K i = 1.0nM) and possesses anti-inflammatory properties when administered orally in an in vivo murine inflammation model. 4 This novel C-3 amido indole and its cyclized and conformationally constrained indolopyridone cannabinoid receptor modulators 1 and 2 are derivatives of indole-3-carboxylates. The morpholino acid, 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid (3) is an advanced core intermediate en route to both of these compounds.…”

“…[2][3][4] In our search for novel cannabinoid receptor modulators, it was discovered that 7-methoxy-2-methyl-1-(2-morpholinoethyl)-N-((1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-indole-3-carboxamide 1 binds selectively to the CB2 receptor and displays excellent in vivo potency against LPS induced TNF-α release in murine models of cytokine production. 3 Further optimization led to a novel cannabinoid ligand 2 which shows high affinity for the CB2 receptor (K i = 1.0nM) and possesses anti-inflammatory properties when administered orally in an in vivo murine inflammation model.…”