ABSTRACT
Metabolites generated from cellular and tissue metabolism have been rediscovered in recent years as signalling molecules. They may act as cofactor of enzymes or be linked to proteins as post-translational modifiers. They also act as ligands for specific receptors, highlighting that their neglected functions have, in fact, a long standing in evolution. Lactate is one such metabolite that has been considered for long time a waste product of metabolism devoid of any biological function. However, in the past 10 years, lactate has gained much attention in several physio-pathological processes. Mechanisms of sensing and signalling have been discovered and implicated in a broad range of diseases, from cancer to inflammation and fibrosis, providing opportunities for novel therapeutic avenues. Here, we review some of the most recently discovered mechanisms of lactate sensing and signalling.
Subject(s)
Lactic Acid , Neoplasms , Humans , Inflammation , Lactic Acid/metabolism , Neoplasms/metabolism , Signal Transduction/geneticsABSTRACT
A model compound was designed to study the relative orientation of enol silane and carbonyl moieties in the Mukaiyama aldol reaction. The cyclization must proceed with either a synclinal or an antiperiplanar orientation of the aldehyde with respect to the enol silane. These two orientations lead to diastereomeric products, thus allowing for unambiguous correlation between product configuration and transition-state geometry. As steric bias is minimal, the product distribution should reflect the intrinsic preferences for reactant geometry in the transition state. Cyclizations of the model compound showed a modest preference for reaction via an antiperiplanar (open transition state) orientation of reactants in the presence of a wide range of Lewis acids (TiCl4, SnCl4, SnCl2, BF3OEt2, TMSBr, trityl perchlorate, EtAlCl2) and triflic acid. The cyclizations promoted by tin(II) salts were syn-selective and dependent on the nature of the counterion. Fluoride ion promoted reactions were anti-selective and were independent of the nature of the cation.
ABSTRACT
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Subject(s)
Amides/chemical synthesis , Aminopyridines/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Thiophenes/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Male , Models, Molecular , Prothrombin Time , Rats , Rats, Wistar , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Venous Thrombosis/drug therapy , ortho-Aminobenzoates/pharmacokinetics , ortho-Aminobenzoates/pharmacologyABSTRACT
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , 3-Phosphoinositide-Dependent Protein Kinases , Drug Design , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesisABSTRACT
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Subject(s)
Amides/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Thiophenes/chemistry , Amides/chemistry , Animals , Crystallography, X-Ray , Dogs , Humans , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
Subject(s)
Anti-HIV Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , CCR5 Receptor Antagonists , Mitoguazone/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
Compound 2 was identified by high throughput screening as a novel PAI-1 inhibitor. Systematic optimization of the A, B, and C segments of 2 resulted in the identification of a more potent compound 39 with good oral bioavailability. The synthesis and SAR data are presented in this report.
Subject(s)
Piperazines/chemical synthesis , Piperazines/pharmacology , Plasminogen Activator Inhibitor 1/chemistry , Animals , Blood Coagulation Tests , Drug Evaluation, Preclinical , Fibrinolysis/drug effects , Molecular Structure , Plasminogen Activator Inhibitor 1/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here.