ABSTRACT
The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.
Subject(s)
Drug Design , Drug Discovery/methods , Small Molecule Libraries/chemistry , Cooperative Behavior , Drug Industry/organization & administration , Drug Industry/trends , Humans , Molecular ConformationABSTRACT
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)2Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
Subject(s)
Cathepsin K/antagonists & inhibitors , Cyclohexanes/chemical synthesis , Indazoles/chemical synthesis , Animals , Blood Proteins/metabolism , Cells, Cultured , Cyclohexanes/pharmacokinetics , Cyclohexanes/pharmacology , Drug Design , Hepatocytes/metabolism , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Models, Molecular , Protein Binding , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Cathepsin K/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Nitriles/chemistry , Nitriles/pharmacology , Animals , Benzothiazoles/metabolism , Benzothiazoles/pharmacokinetics , Cathepsin K/metabolism , Dogs , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Microsomes, Liver/metabolism , Models, Molecular , Nitriles/metabolism , Nitriles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Subject(s)
Carbolines/pharmacology , Cathepsin K/antagonists & inhibitors , Indoles/pharmacology , Osteoarthritis/drug therapy , Protease Inhibitors/pharmacology , Animals , Carbolines/metabolism , Carbolines/pharmacokinetics , Carbolines/therapeutic use , Cathepsin K/chemistry , Dogs , Humans , Indoles/metabolism , Indoles/pharmacokinetics , Indoles/therapeutic use , Inhibitory Concentration 50 , Male , Models, Molecular , Osteoarthritis/enzymology , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic use , Protein Conformation , Rats , Substrate SpecificityABSTRACT
Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase 13/chemistry , Matrix Metalloproteinase Inhibitors , Zinc/chemistry , Animals , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Osteoarthritis/drug therapy , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.
Subject(s)
Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Formyl Peptide/antagonists & inhibitors , Animals , Chemistry, Pharmaceutical/methods , Chemistry, Physical/methods , Drug Design , Hepatocytes/cytology , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Models, Chemical , Rats , Rats, Sprague-Dawley , Receptors, Formyl Peptide/chemistryABSTRACT
A series of pyrazole inhibitors of the human FPR1 receptor have been identified from high throughput screening. The compounds demonstrate potent inhibition in human neutrophils and attractive physicochemical and in vitro DMPK profiles to be of further interest.
Subject(s)
Pyrazoles/pharmacology , Receptors, Formyl Peptide/antagonists & inhibitors , Drug Discovery , Humans , Neutrophils/drug effects , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Zinc/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Matrix Metalloproteinase 13/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel approach to inhibition of the alphavbeta3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Animals , Binding Sites , Computer Simulation , Drug Design , Humans , Integrin alphaVbeta3/metabolism , Oligopeptides/chemistry , Rats , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors.
Subject(s)
Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemistry , Cathepsins/metabolism , Computer Simulation , Crystallography, X-Ray , Drug Design , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.
Subject(s)
Cathepsin L/antagonists & inhibitors , Cathepsin L/chemistry , Nitriles/chemical synthesis , Animals , Cartilage, Articular/pathology , Catalysis , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Ligands , Mice , Mice, Transgenic , Nitriles/chemistry , Nitriles/pharmacology , Peptides/chemical synthesis , Peptides/pharmacology , Proteins/chemistry , Structure-Activity RelationshipABSTRACT
A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Cathepsin K , Cathepsins/chemistry , Chemistry, Pharmaceutical/methods , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Lysosomes/enzymology , Models, Chemical , Molecular Structure , Osteoarthritis/drug therapy , Osteoclasts , Osteoporosis/drug therapy , Pyrimidines/chemistry , Structure-Activity Relationship , Technology, Pharmaceutical/methodsABSTRACT
A quantitative assay involving the reaction of nitriles with glutathione and cysteine has been used as a simple in vitro screen to assess potential toxicity risk of candidate compounds in drug discovery. Studies have indicated that, when benchmarked with selected compounds, the reaction of the nitriles with glutathione can provide a useful tool for deciding whether or not to progress compounds in the absence of radiolabelling studies.
Subject(s)
Drug Discovery , Nitriles/toxicity , Cysteine/analysis , Cysteine/toxicity , Glutathione/analysis , Glutathione/toxicity , Molecular Structure , Nifedipine/analogs & derivatives , Nifedipine/pharmacology , Nitriles/analysisABSTRACT
Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.
Subject(s)
Glycogen Phosphorylase/antagonists & inhibitors , Pyrroles/pharmacology , Animals , Crystallography, X-Ray , Humans , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
Using structure-based design, a new class of inhibitors of protein tyrosine phosphatase-1B (PTP1B) has been identified, which incorporate the 1,2,5-thiadiazolidin-3-one-1,1-dioxide template.