ABSTRACT
Fosmanogepix (APX001) is a first-in-class prodrug molecule that is currently in Phase 2 clinical trials for invasive fungal infections. The active moiety manogepix (APX001A) inhibits the novel fungal protein Gwt1. Gwt1 catalyzes an early step in the GPI anchor biosynthesis pathway. Here we describe the synthesis and evaluation of 292 new and 24 previously described analogs that were synthesized using a series of advanced intermediates to allow for rapid analoging. Several compounds demonstrated significantly (8- to 32-fold) improved antifungal activity against both Cryptococcus neoformans and C. gattii as compared to manogepix. Further in vitro characterization identified three analogs with a similar preliminary safety and in vitro profile to manogepix and superior activity against Cryptococcus spp.
Subject(s)
Aminopyridines/pharmacology , Antifungal Agents/pharmacology , Cryptococcus/drug effects , Isoxazoles/pharmacology , Saccharomyces cerevisiae Proteins/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Dose-Response Relationship, Drug , Fungal Proteins , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Microbial Sensitivity Tests , Molecular Structure , Saccharomyces cerevisiae Proteins/metabolism , Structure-Activity RelationshipABSTRACT
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
Subject(s)
Antifungal Agents/pharmacology , Calcineurin Inhibitors/pharmacology , Tacrolimus/analogs & derivatives , Tacrolimus/pharmacology , Animals , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacokinetics , Antifungal Agents/toxicity , Aspergillus fumigatus/drug effects , Calcineurin Inhibitors/chemical synthesis , Calcineurin Inhibitors/pharmacokinetics , Calcineurin Inhibitors/toxicity , Chlorocebus aethiops , Hep G2 Cells , Humans , Interleukin-2/metabolism , Jurkat Cells , Tacrolimus/chemical synthesis , Tacrolimus/pharmacokinetics , Tacrolimus/toxicity , Tacrolimus Binding Protein 1A/chemistry , Vero CellsABSTRACT
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Histamine Antagonists/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Histamine H3/chemistry , Sulfones/chemistry , Animals , Area Under Curve , Brain/metabolism , Central Nervous System/drug effects , Chemistry, Pharmaceutical/methods , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Histamine Antagonists/pharmacokinetics , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Pyrrolidines/antagonists & inhibitors , Rats , Sleep/drug effects , Temperature , Wakefulness/drug effectsABSTRACT
Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which the preformed, heavily functionalized pyran rings A and C are united by "pyran annulation", the TMSOTf-promoted reaction between a hydroxyallylsilane appended to the A-ring fragment and an aldehyde contained in the C-ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.
Subject(s)
Bryostatins/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Bryostatins/chemistry , Pyrans/chemistry , StereoisomerismABSTRACT
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Subject(s)
Biphenyl Compounds/chemistry , Drug Design , Drug Inverse Agonism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Animals , Histamine Antagonists/administration & dosage , Histamine Antagonists/pharmacokinetics , Humans , Male , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thirst/drug effects , Wakefulness/drug effectsABSTRACT
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Subject(s)
Alkaloids/pharmacokinetics , Chemistry, Pharmaceutical/methods , Histamine Antagonists/pharmacology , Receptors, Histamine H3/chemistry , Animals , Binding, Competitive/drug effects , Central Nervous System/drug effects , Drug Design , Histamine Antagonists/chemistry , Kinetics , Models, Chemical , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Amines/chemical synthesis , Amines/pharmacology , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Alkaloids/chemistry , Amines/chemistry , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Histamine Agonists/pharmacology , Histamine H3 Antagonists/metabolism , Humans , Kinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
[reaction: see text] A reaction process for the asymmetric construction of a variety of cis or trans disubstituted pyrans is described. This sequences allows for the asymmetric convergent union of two aldehydes with silyl-stannane reagent 1 in a two-step process: catalytic asymmetric allylation of the first aldehyde using 1 with a BITIP catalyst, followed by reaction of the alcohol so obtained with a second aldehyde and TMSOTf.