SID 26681509

IC50: 56 nM

SID 26681509 is a potent and reversible human cathepsin L inhibitor.

The cathepsins have been found to comprise a family of lysosomal protease enzymes whose primary functions, such as protein degradation, play a keyl role in normal cellular homeostasis. Overexpression of cathepsin L and/or abnormal activity has been implicated in a number of disease states.

In vitro: SID 26681509 was found to inhibit human cathepsin L with an IC50 of 56 nM. After preincubation with enzyme for 1, 2, and 4 h before substrate addition, SID 26681509 showed increasing potency, with IC50 values falling to 7.5, 4.2, and 1.0 nM, respectively, indicating a slow onset of inhibition. SID 26681509 was also observed to be nontoxic to human aortic endothelial cells up to 100 μM. SID 26681509 was active in an in vitro propagation assay against P. falciparum with an IC50 of 15.4 μM. Additionally, the thiocarbazate inhibitor was toxic toward L. major promastigotes with an IC50 of 12.5 μM [1].

In vivo: SID 26681509 showed a lack of toxicity to zebrafish in a live organism assay at 100 μM [1].

Clinical trial: N/A

Reference:
[1] Shah PP,Myers MC,Beavers MP,Purvis JE,Jing H,Grieser HJ,Sharlow ER,Napper AD,Huryn DM,Cooperman BS,Smith AB 3rd,Diamond SL.  Kinetic characterization and molecular docking of a novel, potent, and selective slow-binding inhibitor of human cathepsin L. Mol Pharmacol.2008 Jul;74(1):34-41.

Thoracic Injury Risk Curves for Rib Deflections of the SID-IIs Build Level D.[Pubmed:27871106]

Stapp Car Crash J. 2016 Nov;60:545-580.

Injury risk curves for SID-IIs thorax and abdomen rib deflections proposed for future NCAP side impact evaluations were developed from tests conducted with the SID-IIs FRG. Since the floating rib guide is known to reduce the magnitude of the peak rib deflections, injury risk curves developed from SID-IIs FRG data are not appropriate for use with SID-IIs build level D. PMHS injury data from three series of sled tests and one series of whole-body drop tests are paired with thoracic rib deflections from equivalent tests with SID-IIs build level D. Where possible, the rib deflections of SID-IIs build level D were scaled to adjust for differences in impact velocity between the PMHS and SID-IIs tests. Injury risk curves developed by the Mertz-Weber modified median rank method are presented and compared to risk curves developed by other parametric and non-parametric methods.

Joint position statement on "Nutraceuticals for the treatment of hypercholesterolemia" of the Italian Society of Diabetology (SID) and of the Italian Society for the Study of Arteriosclerosis (SISA).[Pubmed:27956024]

Nutr Metab Cardiovasc Dis. 2017 Jan;27(1):2-17.

AIM: Evidence showed that LDL-cholesterol lowering is associated with a significant cardiovascular risk reduction. The initial therapeutic approach to hypercholesterolemia includes dietary modifications but the compliance to recommendations is often inadequate. Some dietary components with potential cholesterol-lowering activity are present in small amounts in food. Therefore, in recent years the use of "nutraceuticals" (i.e., nutrients and/or bioactive compounds with potential beneficial effects on human health) has become widespread. Such substances may be added to foods and beverages, or taken as dietary supplements (liquid preparations, tablets, capsules). In the present manuscript, the cholesterol-lowering activity of some nutraceuticals (i.e. fiber, phytosterols, soy, policosanol, red yeast rice and berberine) will be discussed along with: 1) the level of evidence on the cholesterol-lowering efficacy emerging from clinical trial; 2) the possible side effects associated with their use; 3) the categories of patients who could benefit from their use. DATA SYNTHESIS: Based on the current literature, the cholesterol-lowering effect of fiber, phytosterols and red yeast rice is consistent and supported by a good level of evidence. Over berberine, there is sufficient evidence showing significant cholesterol-lowering effects, although the results come from studies carried out almost exclusively in Asian populations. Data on the effects of soy are conflicting and, therefore, the strength of recommendation is quite low. The evidence on policosanol is inconclusive. CONCLUSION: Although health benefits may arise from the use of nutraceuticals with cholesterol-lowering activity, their use might be also associated with possible risks and pitfalls, some of which are common to all nutraceuticals whereas others are related to specific nutraceuticals.

Comparison of calculated and experimentally determined SID of CP and AA in complex diets differing in AA contents for grower finisher pigs.[Pubmed:28052453]

J Anim Physiol Anim Nutr (Berl). 2017 Oct;101(5):e297-e302.

In practice, the content of standardized ileal digestible AA in complex feeds for pigs is calculated on the basis of tabulated values for individual feedstuffs. It comes into question, however, whether this truly reflects an accurate content based upon the estimate made for the individual feedstuffs. The objective of this study was to compare standardized ileal digestibility (SID) of crude protein (CP) and selected AA in complex feeds for grower and finisher pigs either calculated or experimentally determined. Six diets with increasing AA levels were prepared for grower (BW from 30 to 70 kg) and finisher (BW from 70 to 120 kg) feed. Crystalline L-lys, DL-met and L-thr were added to both diets, L-trp and L-val only to the grower feed. SID of both CP and AA was calculated from feed tables and experimentally determined in six adult minipigs (MINILEWE) with ileorectal anastomosis. With increasing AA levels, experimentally determined SID of supplemented AA increased (p < 0.05), but SID of CP (p >/= 0.05) was not affected. In both grower and finisher feed, calculated and experimentally determined SID of CP, Met, Cys, Trp, Ile and Tyr differed by more than 2% units, but those of Lys and His only in the finisher feed. Yet this effect was not directly consistent. The margin of error following estimation of SID of AA via tabulated values for individual feedstuffs, however, seems to be acceptable for practical use.

Incidence, prevalence, costs and quality of care of type 1 diabetes in Italy, age 0-29 years: The population-based CINECA-SID ARNO Observatory, 2002-2012.[Pubmed:27817991]

Nutr Metab Cardiovasc Dis. 2016 Dec;26(12):1104-1111.

BACKGROUND AND AIMS: To assess temporal trend in incidence (2003-12) and prevalence (2002-12) of type 1 diabetes in children and young adults, direct costs and selected indicators of quality of care under the coverage of the universalistic Italian National Health System (NHS). METHODS AND RESULTS: The ARNO Observatory, a healthcare monitoring system based on administrative data, identified a population-based multiregional cohort of subjects aged 0-29 years. Type 1 diabetes was defined by at least two prescriptions of insulin over 12 months and continuous insulin-treatment in the following year. Indicators of quality of care and directs costs were assessed in persons with diabetes and in people without diabetes, individually matched for age, gender and health unit (1:4 ratio). We identified 2357 incident cases of type 1 diabetes aged 0-29 years (completeness of ascertainment, 99%). Incidence rates were similar in ages 0-14 (15.8, 95% CI 14.9-16.8) and 15-29 years (16.3, 15.4-17.2), with no significant trend. Prevalence increased from 137 to 166.9/100,000, particularly in the age 15-29 years. Direct costs accounted for euro 2117 in persons with diabetes and euro 292 in control individuals. A statistically significant decreasing trend in hospitalization for acute complications was evident (p < 0.001), which was almost completely due to ketoacidosis. People with at least one HbA1c measurement over the year were 48.5%. CONCLUSION: We showed high incidence and increasing prevalence of type 1 diabetes in young adults in Italy, which impact on direct costs under the universalistic coverage of the NHS.

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor.[Pubmed:18060772]

Bioorg Med Chem Lett. 2008 Jan 1;18(1):210-4.

Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (-)-11 and (-)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin L in the low nanomolar range.

Kinetic characterization and molecular docking of a novel, potent, and selective slow-binding inhibitor of human cathepsin L.[Pubmed:18403718]

Mol Pharmacol. 2008 Jul;74(1):34-41.

A novel small molecule thiocarbazate (PubChem SID 26681509), a potent inhibitor of human cathepsin L (EC 3.4.22.15) with an IC(50) of 56 nM, was developed after a 57,821-compound screen of the National Institutes of Health Molecular Libraries Small Molecule Repository. After a 4-h preincubation with cathepsin L, this compound became even more potent, demonstrating an IC(50) of 1.0 nM. The thiocarbazate was determined to be a slow-binding and slowly reversible competitive inhibitor. Through a transient kinetic analysis for single-step reversibility, inhibition rate constants were k(on) = 24,000 M(-1)s(-1) and k(off) = 2.2 x 10(-5) s(-1) (K(i) = 0.89 nM). Molecular docking studies were undertaken using the experimentally derived X-ray crystal structure of papain/CLIK-148 (1cvz. pdb). These studies revealed critical hydrogen bonding patterns of the thiocarbazate with key active site residues in papain. The thiocarbazate displayed 7- to 151-fold greater selectivity toward cathepsin L than papain and cathepsins B, K, V, and S with no activity against cathepsin G. The inhibitor demonstrated a lack of toxicity in human aortic endothelial cells and zebrafish. In addition, the thiocarbazate inhibited in vitro propagation of malaria parasite Plasmodium falciparum with an IC(50) of 15.4 microM and inhibited Leishmania major with an IC(50) of 12.5 microM.

SID 26681509 is a potent, reversible, competitive, and selective inhibitor of human cathepsin L with an IC50 of 56 nM. SID 26681509 inhibits in vitro propagation of malaria parasite Plasmodium falciparum and inhibits Leishmania major with IC50s of 15.4 μM and 12.5 μM, respectively. SID 26681509 shows no inhibitory activity against cathepsin G.

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