Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Ethers/pharmacology , Lactones/pharmacology , Pyrimidines/pharmacology , Receptors, Nicotinic/metabolism , Ethers/chemical synthesis , Ethers/chemistry , Humans , Lactones/chemical synthesis , Lactones/chemistry , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
Azepines/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxazocines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Azepines/chemical synthesis , Azepines/chemistry , Humans , Molecular Structure , Oxazocines/chemical synthesis , Oxazocines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship
Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.
A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.
A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.
Histamine Antagonists/chemistry , Pyridines/chemistry , Receptors, Histamine H3/chemistry , Animals , Haplorhini , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacokinetics , Humans , Mice , Mice, Inbred ICR , Microsomes, Liver/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Receptors, Histamine H3/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Structure-Activity Relationship , Trans-Activators/metabolism , Transcriptional Regulator ERG
