ABSTRACT
We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.
ABSTRACT
In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
Subject(s)
Amino Alcohols/pharmacology , Receptors, Lysosphingolipid/agonists , Administration, Oral , Amino Alcohols/administration & dosage , Animals , Mice , Structure-Activity RelationshipABSTRACT
In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
Subject(s)
Amides/chemical synthesis , Imidazoles/chemical synthesis , Receptors, Lysosphingolipid/agonists , Amides/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Fingolimod Hydrochloride , Imidazoles/pharmacology , Mice , Propylene Glycols/chemistry , Propylene Glycols/pharmacology , Protein Subunits/agonists , Protein Subunits/physiology , Receptors, Lysosphingolipid/physiology , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/pharmacologyABSTRACT
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Receptors, Lysosphingolipid/agonists , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Humans , Imidazoles/chemistry , Mice , Structure-Activity RelationshipABSTRACT
A novel series of potent inhibitors of Ras farnesyl transferase possessing a 1,2,4-triazole pharmacophore is described. These inhibitors were discovered from a parallel synthesis effort and were subsequently optimized to in vitro IC(50) value of less than 1nM.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase/antagonists & inhibitors , Triazoles/chemical synthesis , Amino Acid Sequence , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/genetics , Genes, ras , Models, Molecular , Molecular Conformation , Oligopeptides/chemistry , Triazoles/pharmacologyABSTRACT
Solid-phase synthesis of imidazolyl-beta-amino acid derivatives is described. Several analogs demonstrated moderate inhibition of geranylgeranyl protein transferase type I (GGPT I).
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Amino Acids/chemical synthesis , Amino Acids/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
