Garry R. Smith

Stereochemistry of mephedrone neuropharmacology: enantiomer‐specific behavioural and neurochemical effects in rats

Synthetic cathinones, commonly referred to as ‘bath salts’, are a group of amphetamine‐like drugs gaining popularity worldwide. 4‐Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate‐type releaser at monoamine transporters. Similar to other cathinone‐related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R‐mephedrone (R‐MEPH) and S‐mephedrone (S‐MEPH).

The role of sulfamide derivatives in medicinal chemistry: a patent review (2006-2008).

Background: The sulfamide (R2NSO2NR2) functionality is an acceptable functional group in medicinal chemistry when incorporated into putative small-molecule therapeutics, as it has the potential to form several electrostatic interactions with protein and other targets. The clinically-useful broad spectrum antibiotic doripenem contains a mono-substituted sulfamide. The sulfamide functional group is often found to substitute for sulfonamide, sulfamate or urea functionality. Objective/method: During the period of 2006 – 2008, there were nine published patents in which all or most reported compounds contained the sulfamide functional group. There are also patents in which the structures disclosed contain a cyclic sulfamide functional group. Further, there are patents published during this timeframe that contain only a few sulfamide-containing examples, typically as a bioisosteric replacement for a sulfonamide moiety. In this review, we focus on those published patents in which most compounds disclosed are sulfamides and only briefly highlight examples in which sulfamides are included among a large list of other suitable functionalities. Conclusion: While the sulfamide functionality is still fairly under-represented in medicinal chemistry, it is a valuable and versatile group that will gain increasing acceptance and favor in the future.

Stereochemistry of mephedrone neuropharmacology

Synthetic cathinones, commonly referred to as ‘bath salts’, are a group of amphetamine‐like drugs gaining popularity worldwide. 4‐Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate‐type releaser at monoamine transporters. Similar to other cathinone‐related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R‐mephedrone (R‐MEPH) and S‐mephedrone (S‐MEPH).

Riluzole prodrugs for melanoma and ALS: Design, synthesis, and in vitro metabolic profiling

Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.

Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain

Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized hydroxyquinolines. Seventy-two compounds had IC50 values below 10 μM, with the best compound exhibiting submicromolar inhibition (IC50 = 0.8 μM). Structure–activity relationship trends showed that the enzyme tolerates various substitutions at R1 but has a clear preference for bulky aryl amide groups at R2, while methylation at R3 increased inhibitor potency. Evaluation of the most potent compounds in an ADME panel showed that these compounds possess poor solubility at pH 6.8, but display excellent solubility at low pH, suggesting that oral dosing may be possible. Our data show the potential of quinolinol compounds as BoNT therapeutics due to their good in vitro potencies and favorable ADME properties.

Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

In vivo canine cardiac electrophysiologic profile of 1,4-benzodiazepine IKs blockers.

&NA; Previous cardiac electrophysiologic studies of blockers of the slowly activating delayed rectifier (IKs) current have focused primarily on ventricular repolarization. This report summarizes an extensive in vivo cardiac electrophysiologic profile of four 1,4‐ benzodiazepine IKs blocker analogues (L‐761334, L‐763540, L‐761710, and L‐768673) in dogs. At 3.0 mg/kg intravenously, all four analogues elicited 14.5%‐21.4% increases in ventricular refractoriness and 19.2%‐22.6% increases in QTc interval. Concomitant 11.1%‐13.5% increases in atrial refractoriness were noted with all four analogues. Decreases in sinus heart rate of 8.4%‐17.3% were noted with all four compounds. No effects on atrial, His Purkinje, ventricular conduction or atrial and ventricular excitation were observed. One analogue, L‐761710, significantly delayed atrioventricular (AV) nodal conduction (40.7 ± 17.4% increase in atrial‐to‐His interval) and increased the AV conduction system functional refractory period 19.9 ± 6.2%. The lack of effect of the other three 1,4‐ benzodiazepine IKs blockers on AV nodal function at dosages producing comparable effects on atrial and ventricular refractoriness suggest that the AV nodal effects of L‐761710 were unrelated to IKs blockade. These findings indicate IKs plays important roles in both atrial and ventricular refractoriness as well as pacemaker function in the dog heart, suggesting potential utility for IKs blockers in the treatment of atrial and ventricular arrhythmias.

Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates.

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100-1000 μM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 μM) and racemate (100 μM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 μM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaines behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 μM) produced EPC that was abolished when S-MEPH (100 μM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 μM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 μM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaines addictive-like behaviors without producing rewarding effects of its own.

Hit Triage Using Efficiency Indices after Screening of Compound Libraries in Drug Discovery

Fragment-based drug discovery (FBDD) is an important new tool to understand the molecule basis of ligand-biological target interactions. By combining optimal fragments, it is often possible to construct larger molecular weight compounds that have greater potency in a shorter period of time than can been achieved by the initial screening of larger molecular weight compound libraries. Alternatively, if screening of more traditional larger libraries has occurred, then it may be possible to analyze the data during the process of hit triage in such as way as to essentially adopt a fragment-based approach in reverse. In this review, we highlight general principles associated with the efficiency indices such as Ligand Efficiency (LE) in which screening data is normalized for biophysical properties such as molecular size. We further focus on the concept of Fit Quality (FQ), which standardizes LE values across molecular weight for more realistic, direct comparison. Using these simple concepts, one can apply FBDD routinely in the stage of hit triage when evaluating the data obtained after screening of compound libraries in drug discovery.

Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the β-exosite.

Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC(50) of 0.23 μM. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.