ABSTRACT
The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16â mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1â mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Oxazines/pharmacology , Thiazines/pharmacology , Amyloid Precursor Protein Secretases/deficiency , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/deficiency , Aspartic Acid Endopeptidases/metabolism , Dogs , Dose-Response Relationship, Drug , Drug Design , Hepatocytes/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Oxazines/chemistry , Rats , Structure-Activity Relationship , Thiazines/administration & dosage , Thiazines/chemistryABSTRACT
Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Drug Design , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analgesics/chemistry , Analgesics/pharmacokinetics , Animals , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N, N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine ß-secretase inhibitor 2.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Diethylamines/pharmacology , Enzyme Inhibitors/pharmacology , Fluorine/pharmacology , Thiazines/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Cyclization , Diethylamines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fluorine/chemistry , Humans , Molecular Structure , Thiazines/chemical synthesis , Thiazines/chemistryABSTRACT
NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases.
Subject(s)
Analgesics/pharmacology , Cyclohexanols/pharmacology , Drug Discovery , Pain/drug therapy , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Administration, Oral , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Brain/metabolism , Cyclohexanols/administration & dosage , Cyclohexanols/chemistry , Dose-Response Relationship, Drug , Formaldehyde , HEK293 Cells , Humans , Mice , Molecular Structure , Pain/chemically induced , Rats , Structure-Activity RelationshipABSTRACT
Both diastereomeric right-handed (P) and left-handed (M) 310-helices exist in homopeptides having twelve chiral centers at the side-chain bicyclic skeletons.
