The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.
A detailed molecular mechanism has recently been described for the phase transfer catalyzed enantioselective alkylation of an enolate with use of the chiral quaternary cinchonidinium salt 1a. 1,2 This reaction was illustrated by a variety of examples in which a series of (S)-R-amino acid derivatives (both natural and unnatural) was prepared with enantioselectivities in the range 400:1 to 60:1 by alkylation of the tert-butyl glycinate-benzophenone Schiff base. 3 In the mechanistic model contact ion pairing takes place selectively between the anionic oxygen of the enolate and just one of the tetrahedral faces of the cationic nitrogen of 1a (for steric reasons). In addition, considerable van der Waals attraction occurs between the enolate and a complementary binding site on the quaternary ammonium cation within the contact ion pair. The combination of electrostatic and van der Waals binding results in a highly structured contact ion pair in which only one face of the nucleophilic R carbon of the enolate is accessible to the electrophilic alkylating species. 1 This mechanistic picture provides a logical explanation for the absolute stereochemical course of the catalytic alkylation process and also the very high levels of enantioselectivity which are observed. In this paper we demonstrate that this remarkably enantioselective alkylation catalyst can be applied to other enolates and that the enantioselectivity varies in a predictable way with the electronic effect of remote substituents on the enolate. In addition, we present an analysis of the alkylation process that underscores the importance of charge density and entropy in determining the level of enantioselectivity.The β,γ-unsaturated ester 2 was prepared from 4,4′-bis-(dimethylamino)benzophenone (Michler's ketone) by the following sequence: (1) reaction with γ-lithiated tert-butyl propiolate (from n-BuLi on the propiolate ester in THF at -78 °C) in THF at -15 °C for 20 h (68%); (2) catalytic reduction with 1 atm of H 2 over 5% Pd-BaSO 4 at 23 °C for 20 min (91%); and (3) dehydration with CH 3 SO 2 Cl-Et 3 N-4-N,N-(dimethylamino)pyridine in CH 2 Cl 2 at 0 °C for 30 min (86%). Reaction of 2 in 1:1 CH 2 Cl 2 -Et 2 O solution containing 10 mol % of chiral ammonium bromide 1b with various alkyl bromides or iodides
The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.
In the past eight years, numerous series of small molecule CXCR2 and CXCR1 antagonists have been disclosed. These compounds have proved to be effective inhibitors of ELR+ chemokine-induced chemotaxis of neutrophils and other immune cells in vitro and have also been efficacious in several animal models of inflammatory disease. Although some of these compounds have been reported to be in clinical development, no data on clinical studies in patients with inflammatory disease has been revealed to date. This review details the medicinal chemistry and pharmacology of the aforementioned antagonist series.
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