ABSTRACT
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cinnamates/chemical synthesis , Cinnamates/pharmacology , Hygromycin B/analogs & derivatives , Hygromycin B/chemical synthesis , Hygromycin B/pharmacology , Microbial Sensitivity TestsABSTRACT
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
Subject(s)
Adenosine Triphosphate/physiology , Amides/chemical synthesis , Aminoquinolines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Amides/pharmacokinetics , Amides/pharmacology , Aminoquinolines/pharmacokinetics , Aminoquinolines/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Mice , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Pyrimidines/chemistry , Pyrrolidines/chemistry , Spiro Compounds/chemistry , Animals , Enzyme Stability/drug effects , Matrix Metalloproteinase 13/metabolism , Protease Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Rats , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrimidinones/chemistry , Animals , Fibrosis/drug therapy , Fibrosis/pathology , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Molecular Weight , Rats , Salts/chemistry , Sodium/chemistry , Structure-Activity RelationshipABSTRACT
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Subject(s)
Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Matrix Metalloproteinases/metabolism , Protease Inhibitors/pharmacology , Pyrans/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.