ABSTRACT
Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
Subject(s)
NAV1.7 Voltage-Gated Sodium Channel , Pain , Animals , Humans , Macaca mulatta , Nociception , NociceptorsABSTRACT
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Drug Discovery , Imidazoles/pharmacology , Morpholines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Arthritis, Rheumatoid/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Models, Molecular , Molecular Structure , Morpholines/chemical synthesis , Morpholines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.
Subject(s)
Benzimidazoles/chemistry , Receptors, Glucagon/antagonists & inhibitors , Receptors, Glucagon/chemistry , Administration, Oral , Animals , Benzimidazoles/pharmacokinetics , CHO Cells , Chemistry, Pharmaceutical/methods , Cricetinae , Cricetulus , Diabetes Mellitus, Experimental/metabolism , Glucagon/chemistry , Humans , Inhibitory Concentration 50 , Macaca mulatta , Mice , Mice, TransgenicABSTRACT
HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV-1/drug effects , Oxadiazoles/chemistry , Cell Line, Tumor , Drug Resistance, Multiple, Viral , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , HIV-1/isolation & purification , Humans , Indinavir/analogs & derivatives , Indinavir/chemical synthesis , Indinavir/chemistry , Indinavir/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Pyridines/chemistry , StereoisomerismABSTRACT
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.
