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2.
Bioorg Med Chem Lett ; 16(4): 978-83, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16290936

ABSTRACT

Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.


Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Semicarbazones/pharmacology , Animals , Cathepsin K , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrogen-Ion Concentration , Hydrolysis , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Solubility , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 15(15): 3540-6, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15982880

ABSTRACT

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.


Subject(s)
Amides/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Ketones/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Binding Sites , Biological Availability , Bone Resorption/drug therapy , Bone Resorption/metabolism , Cathepsin K , Cathepsins/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Disease Models, Animal , Hypocalcemia/drug therapy , Hypocalcemia/metabolism , Ketones/pharmacokinetics , Ketones/pharmacology , Rats , Rats, Wistar , Solubility , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 15(12): 3039-43, 2005 Jun 15.
Article in English | MEDLINE | ID: mdl-15896958

ABSTRACT

Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.


Subject(s)
Cathepsins/antagonists & inhibitors , Cyanamide/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Osteogenesis/drug effects , Animals , Binding Sites , Bone Resorption , Cathepsin B/antagonists & inhibitors , Cathepsin H , Cathepsin K , Cathepsin L , Crystallography, X-Ray , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/chemical synthesis , Disease Models, Animal , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 15(7): 1815-9, 2005 Apr 01.
Article in English | MEDLINE | ID: mdl-15780613

ABSTRACT

Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition.


Subject(s)
Cathepsins/antagonists & inhibitors , Cyanamide/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Animals , Cathepsin K , Crystallography, X-Ray , Cyclization , Cysteine Proteinase Inhibitors/pharmacology , Inhibitory Concentration 50 , Pyrrolidines/chemistry , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 14(19): 4897-902, 2004 Oct 04.
Article in English | MEDLINE | ID: mdl-15341947

ABSTRACT

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.


Subject(s)
Amides/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Binding Sites , Cathepsin K , Cathepsins/chemistry , Humans , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 14(13): 3425-9, 2004 Jul 05.
Article in English | MEDLINE | ID: mdl-15177446

ABSTRACT

The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.


Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Aldehydes/pharmacology , Binding Sites/drug effects , Carbamates/chemistry , Cathepsin K , Humans , Inhibitory Concentration 50 , Norleucine/chemistry , Protease Inhibitors/pharmacology , Structure-Activity Relationship
8.
J Med Chem ; 47(3): 588-99, 2004 Jan 29.
Article in English | MEDLINE | ID: mdl-14736240

ABSTRACT

Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis


Subject(s)
Amides/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Ketones/chemical synthesis , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Calcium/blood , Cathepsin K , Cathepsins/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Humans , Ketones/pharmacokinetics , Ketones/pharmacology , Male , Models, Molecular , Molecular Structure , Osteoporosis/metabolism , Rats , Rats, Wistar , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 14(1): 275-8, 2004 Jan 05.
Article in English | MEDLINE | ID: mdl-14684342

ABSTRACT

The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.


Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemistry , Aldehydes/pharmacology , Binding Sites/drug effects , Binding Sites/physiology , Cathepsin K , Cathepsins/metabolism , Protease Inhibitors/pharmacology , Structure-Activity Relationship
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