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Review
. 2013 May 8;113(5):3516-604.
doi: 10.1021/cr100264t. Epub 2013 Feb 25.

The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives

Lukas Wanka  1 , Khalid Iqbal, Peter R Schreiner
Affiliations
Review

The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives

Lukas Wanka et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
This silver sculpture, “cloud gate” in Chicago, Ill reflects the seven drugs on the market today incorporating the adamantane motif. Chicagoans refer to cloud gate as “the bean”, and reserachers at universities near “the bean” have contributed to the elucidation of the mechanisms of action of some of these drugs. Photograph taken by L. Wanka.
Figure 2
Figure 2
Docking of N-hexanoic acid adamantyl amide deoxynojirimycin into the active site and a nearby hydrophobic cleft of glucocerebrosidase. (Yu, Z.; Sawkar, A. R.; Whalen, L. J.; Wong, C. H.; Kelly, J. W. J. Med. Chem. 2007, 50, 94-100.)
Figure 3
Figure 3
Binding modes of aminoadamantanes to Influenza A M2 model peptides. Panel A – C: Amantadine binding inside the pore of M2 transmembrane domain (X-ray diffraction data, pdb code 3c9j). Panel D – F: Rimantadine binding from the outside of the M2 model peptide (representative NMR data, pdf code 2rlf). The drug molecules are shown in red, His and Trp residues in the M2 model peptides are depictes as ball-and-stick models. See text for a discussion.
Figure 4
Figure 4
Sequence comparison between Influenza A and Influenza B M2 proteins. The transmembrane domain is underlined, the proton-gating HXXXW motif is in bold, the Ser residues presumably rendering the BM2 channel amantadine resistant by making the inside of the channel less hydrophobic are bold and in italics.
Figure 5
Figure 5
Saxagliptin (352) comlexed with DPP-IV, pdb code 3bmj. A: Binding location in the Enzyme; B: closeup with Saxagliptin in spacefill; C: closeup showing Saxagliptin as a tube model. See text for discussion.
Figure 6
Figure 6
Crystal structure of hydroxysteroid dehydrogenase inhibitor 375 bound to hHSD-1 (pdb code: 2ilt). A: Full protein with the Ligand depicted in red; B: closeup showing the location of inhibitor binding and residues Tyr177 and Tyr 183 as a tube model; C: closeup with the protein surface omitted for clarity. Yellow: sulfur; red: oxygen, blue: nitrogen, light green: fluorine, deep green: chlorine.
Scheme 1
Scheme 1
Naturally occuring and nature-inspired heteroadamantanes
Scheme 2
Scheme 2
Natural products isolated from plants incorporating an adamantane scaffold
Scheme 3
Scheme 3
Polymantanes isolated frome crude oil
Scheme 4
Scheme 4
Anabolic activity of adamantoates of 19-nortestosterone (Nandrolone) as measured by the weight gain of the levator ani muscle over control (values in mg in brackets) in rats. Values in square brackets: ALOGPs data.
Scheme 5
Scheme 5
Add-on strategy to generate drug candidates incorporating an adamantane moiety
Scheme 6
Scheme 6
Design of activators for glucocerebrosidase
Scheme 7
Scheme 7
Gramicidin S (40) and adamantylated analog (41).
Scheme 8
Scheme 8
Early structural variations of anti-Influenza A drug candidates alongside the amantadine lead. AVI50 values in mg/kg (mouse) given in parentheses.
Scheme 9
Scheme 9
Development of adamantanes and other cage compounds as antiviral agents.
Scheme 10
Scheme 10
Refinement of adamantyl amines and -diamines targeting the Influenza A M2 ion channel. Numbers in parentheses are the relative potencies of the compounds measured as an x-fold increase or decrease in MIC50 compared to amantadine as positive control. 64 – 68: Influenza A (Ishikawa); 69 – 75: Influenza A2/Japan/305/1957 (H2N2). All compounds screened in MDCK cell culture assays.
Scheme 11
Scheme 11
Recently reported aminoadamantanes with anti-Influenza A activity. Numbers in parentheses are potencies relative to amantadine in the same assays.
Scheme 12
Scheme 12
Fluoro-aminoadamantane 96 utilized in the F-NMR structure elucidation of M2TM peptide, aminoadamantanes 94 and 97–100 assayed in a Trp41 fluorescence-quenching assay. Values in parentheses are the binding constants to the model peptide and their potencies against Influenza A/Japan/305/57 (H2N2) as observed in an MDCK cell based assay, relative to amantadine
Scheme 13
Scheme 13
Recent channel blockers for amantadine-resistant M2 ion channels. The percentage of remaining M2 channel activity after application of 100 μM compound inhibition.
Scheme 14
Scheme 14
Anti-HSV agents. Values in square brackets: ALOGPs data.
Scheme 15
Scheme 15
2-phenylbenzimidazoles (118–121) and imidazopyridine 122 as anti-HSV 2 agents. Given in parentheses are IC50 values in a cell based assay.
Scheme 16
Scheme 16
Most recent adamantane derivatives with anti-HSV 1 properties. Given in parentheses is the EC50 (in μg/mL) as determined by plaque-reduction assay using Vero cells.
Scheme 17
Scheme 17
Adamantane derivatives displaying anti-hepatitis properties and hexamethyleneamiloride (128)
Scheme 18
Scheme 18
Outline of aminoadamantanes screened for anti-HIV-1 activity. Numbers in parentheses are the EC50 values in cell based assays / the CC50 values (in μM).
Scheme 19
Scheme 19
Modifications of known anti-HIV drugs by adamantane moieties
Scheme 20
Scheme 20
Experimental non-nucleoside inhibitors of HIV reverse transcriptase
Scheme 21
Scheme 21
Semisynthetic anti-HIV compounds incorporating adamantane as lipophilic modifier.
Scheme 22
Scheme 22
Modifications via adding adamantane moieties on known antimalarials
Scheme 23
Scheme 23
Artemisinin and spiroadamantane peroxide screened as antimalarials.
Scheme 24
Scheme 24
SAR of antimalarial spiroadamantane-1,2,4-trioxanes. Numbers in parentheses are the % suppression of P. yoelii parasites in Swiss mice on day 4 after receiving orally 96 mg/kg/day of the drug and the mean survival time in days.
Scheme 25
Scheme 25
Antimalarial compounds for an SAR. Numbers in parentheses are the IC50 values against the Chloroquine-resistant K1 strain of P. falciparum in ng/mL measured in vitro, numbers in square brackets are ALOGPs data.
Scheme 26
Scheme 26
Further developments based upon the spiroadamantane-1,2,4-trioxolane motif.
Scheme 27
Scheme 27
Recent developments of antimalarial 1,2,4-trioxanes.
Scheme 28
Scheme 28
Aminoadamantanes and related compounds screened as tryptanocidals. Numbers in square brackets are ALOGPs data. Values in parentheses represent IC50 and IC90 data in μM. All values detected in vitro using T. brucei (strain 427) cultured in Iscove's medium at pH = 7.4 and 37 °C.
Scheme 29
Scheme 29
Antiparkinsonian agents incorporating the adamantane motif.
Scheme 30
Scheme 30
Selective dopamine-D1 receptor agonist (R,S)-219 and its significantly less active enantiomer, (S,R)-219
Scheme 31
Scheme 31
Adamantane derivatives used to study KATP channels
Scheme 32
Scheme 32
Compounds used to elucidate the pharmacology of AMPA receptors and a homology model of the pore built around IEM-1460.
Scheme 33
Scheme 33
Recent cage compounds studied as NMDAR blockers.
Scheme 34
Scheme 34
CNTF-derived, adamantane-modified peptides that enhance neurogenesis in vitro as well as in vivo and improve learning and memory normal mice.
Scheme 35
Scheme 35
Aminoalkylcyclohexanes as NMDAR antagonists with Memantine as the “template”.
Scheme 36
Scheme 36
Lipophilic GABA analogues
Scheme 37
Scheme 37
Adamantylated peptoids derived from CCK4.
Scheme 38
Scheme 38
Recent developments of small-molecule CCK receptor ligands.
Scheme 39
Scheme 39
Neurotensin receptor antagonists incorporating an adamantane motif.
Scheme 40
Scheme 40
Adamantaneacetyl-D-Tyr(OEt)-Val-Abu-Arg-H, a vasopressin receptor antagonist.
Scheme 41
Scheme 41
Adamantane-based enkephalin-derived peptides and the NPFF receptor antagonist RF9 (281).
Scheme 42
Scheme 42
High-affinity serotonin receptor ligands
Scheme 43
Scheme 43
Lipophilically modified somatostatin analogues
Scheme 44
Scheme 44
Peptide-derived, lipophilic opioid receptor ligands
Scheme 45
Scheme 45
High-affinity ligands for σ-receptors
Scheme 46
Scheme 46
Adamantane modified ligands for estrogen receptors
Scheme 47
Scheme 47
Adamantane amides in the development of P2X7 antagonists
Scheme 48
Scheme 48
Adamantane derived sEH inhibitors.
Scheme 49
Scheme 49
Discovery of the dipeptidyl peptidase IV inhibitor, vildagliptin
Scheme 50
Scheme 50
Discovery of Saxagliptin
Scheme 51
Scheme 51
Enzymatic steps in the large-scale synthesis of Saxagliptin (352)
Scheme 52
Scheme 52
further developments en route to inhibitors of DPP-IV. Asterisks indicate C labels
Scheme 53
Scheme 53
Inhibitors for type 3 17 β-hydroxysteroid dehydrogenase
Scheme 54
Scheme 54
Substrates for HSD1 and HSD2 and 349, an HSD1 inhibitor.
Scheme 55
Scheme 55
Various 11 β-hydroxysteroid dehydrogenase inhibitors
Scheme 56
Scheme 56
Adamantaplatensimycin
Scheme 57
Scheme 57
Development of cisplatin analogues incorporating aminoadamantane ligands.
Scheme 58
Scheme 58
Adaphostin and some of its derivatives
Scheme 59
Scheme 59
Adamantane-derivatives as retinoids. ALOGPs data in square brackets.
Scheme 60
Scheme 60
Recent modifications for retinoid-related molecules (RRMs) incorporating an adamantane substituent.
Scheme 61
Scheme 61
Metabolites of amantadine
Scheme 62
Scheme 62
Memantine and its metabolites
Scheme 63
Scheme 63
Metabolites of Tromantadine
Scheme 64
Scheme 64
Rimantadine and metabolites detected in human urine
Scheme 65
Scheme 65
CCK-B antagonist 385 and its major metabolite
Scheme 66
Scheme 66
Vildagliptin and some of its metabolites.
Scheme 67
Scheme 67
Saxagliptin and major metabolite 457
Scheme 68
Scheme 68
Antimalarial spiroadamantane ozonide OZ277 and its metabolites
Scheme 69
Scheme 69
Adamantyl retinoid 414 (ST1926, AHPC) and two of its metabolites.
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