Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors

Gustin, Darin J.; Sehon, Clark A.; Wei, Jianmei; Cai, Hui; Meduna, Steven P.; Khatuya, Haripada; Sun, Siquan; Gu, Yin; Jiang, Wen; Thurmond, Robin L.; Karlsson, Lars; Edwards, James P.

doi:10.1016/j.bmcl.2005.01.045

Cited by 41 publications

(19 citation statements)

References 12 publications

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“…Further optimization of the compound led to the ketobenzimidazole piperidine moiety, and the lead compound JNJ 10329670 is the first nonpeptidic noncovalent orally available cathepsin S inhibitor (K i ~30 nM), which showed good efficacy in cellular and in a mouse model [202,203]. However, the compound showed lower affinity towards mouse, dog monkey and bovine cathepsin S variants, although no cross reactivity with other human cathepsins was observed even at high concentration (K i > 50 μM; [203]). …”

Section: Development Of Cathepsin S Inhibitorsmentioning

confidence: 99%

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Vasiljeva

Reinheckel²,

Peters³

et al. 2007

CPD

401

180

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The general view on cysteine cathepsins, which were long believed to be primarily involved in intracellular protein turnover, has dramatically changed in last 10 to 15 years. The discovery of new cathepsins, such as cathepsins K, V, X, F and O, and their tissue distribution suggested that at least some of them are involved in very specific cellular processes. Moreover, gene ablation experiments revealed that cathepsins play a vital role in numerous physiological processes, such as antigen processing and presentation, bone remodelling, prohormone processing and wound healing. Their involvement in several pathologies, including osteoporosis, rheumatoid arthritis, osteoarthritis, bronchial asthma and cancer have also been confirmed and today several of them have been validated as relevant targets for therapies. Compounds targeting cathepsins S and K are already in clinical evaluation, whereas others are in experimental phases. The cathepsin K inhibitor AAE-581 (balicatib) as the most advanced of them passed Phase II clinical trials in 2005. In this review, we discuss the current view on cathepsins as an emerging group of targets for several diseases and the development of cathepsin K and S inhibitors for treatment of osteoporosis and various immune disorders.

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Section: Development Of Cathepsin S Inhibitorsmentioning

confidence: 99%

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Vasiljeva

Reinheckel²,

Peters³

et al. 2007

CPD

401

180

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“…Although many other arylpiperazines possess α 1 -adrenergic activity in addition to that of other receptor systems [81][82][83][84], they were not taken into account because α 1 -AR recognition was not a driving force in their design.…”

Section: Arylpiperazinesmentioning

confidence: 99%

Recent Advances in α1-Adrenoreceptor Antagonists as Pharmacological Tools and Therapeutic Agents

Rosini¹,

Bolognesi²,

Giardinà³

et al. 2007

CTMC

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Native alpha(1)-adrenoreceptors (ARs) appear to exist as three different subtypes encoded by three genes, alpha(1A/1a), alpha(1B/1b), and alpha(1D/1d). Historically, the discovery of agents selective for each of the three alpha(1)-AR subtypes has been an active area of medicinal chemistry research because of the wide number of possible therapeutic applications. Initially introduced for the management of hypertension, alpha(1)-AR antagonists have, in fact, become increasingly common in the treatment of benign prostatic hyperplasia (BPH), and are effective therapeutic tools, when characterized by an appropriate uroselective profile. The majority of these derivatives display a competitive mechanism of action and belong to a variety of structural classes, but this review is focused on compounds belonging to the quinazoline, benzodioxane, arylpiperazine, and 1,4-dihydropyridine classes.

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“…24 of these possessed activity against one or more proteases and 20 exhibited anti-plasmodial activity. Compound 39 had IC 50 factors including cross reactivity with the Adrenergic 1 a , 1 b , and 1 d receptors, compound 41 was modified to replace the aryl piperazine with a benzimidazolone derivative resulting in JNJ10329670 (42) [147] with somewhat lower Cathepsin S potency (IC 50 100 nM) but with dramatically better selectivity and 40-75% oral bioavailability [148].…”

Section: Fig (16)mentioning

confidence: 99%

Current Status of Virtual Screening as Analysed by Target Class

Stoermer

2006

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In silico virtual screening for drug discovery has become a hot topic in medicinal chemistry research during the last 5 years, growing from a largely academic pursuit concerned principally with validating the methods used, to a major early-stage technique for lead discovery in the pharmaceutical industry. In this review we highlight a few recent successes in ligand docking associated with virtual screening, paying particular attention to four major target classes of pharmaceutical interest (G Protein-Coupled receptors, nuclear hormone receptors, kinases, proteases). We also discuss some emerging trends in the field, some common limitations, and how they are being overcome.

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Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors

Cited by 41 publications

References 12 publications

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Recent Advances in α1-Adrenoreceptor Antagonists as Pharmacological Tools and Therapeutic Agents

Current Status of Virtual Screening as Analysed by Target Class

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Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors

Cited by 41 publications

References 12 publications

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Recent Advances in &#945;1-Adrenoreceptor Antagonists as Pharmacological Tools and Therapeutic Agents

Current Status of Virtual Screening as Analysed by Target Class

Contact Info

Product

Resources

About

Recent Advances in α1-Adrenoreceptor Antagonists as Pharmacological Tools and Therapeutic Agents