ABSTRACT
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
ABSTRACT
We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 µM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).
ABSTRACT
We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.
Subject(s)
Amides/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Azepines/chemistry , Azepines/pharmacology , Azepines/chemical synthesis , Cyclization , Models, Molecular , Structure-Activity RelationshipABSTRACT
Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.
Subject(s)
Benzimidazoles/chemical synthesis , Oligopeptides/chemistry , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cell Line , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Mimicry , Molecular Structure , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
Subject(s)
Dipeptides/chemical synthesis , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Thiazoles/chemical synthesis , Crystallography, X-Ray , Dipeptides/chemistry , Drug Design , Models, Molecular , Molecular Mimicry , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Quantitative Structure-Activity Relationship , Stereoisomerism , Thiazoles/chemistryABSTRACT
Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa.
Subject(s)
Factor IXa/antagonists & inhibitors , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Thiophenes/pharmacology , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
Structural features of a 5-amidinoindole inhibitor of factor Xa, which displayed modest inhibition of factor IXa were varied to increase potency and improve selectivity for factor IXa.
