ABSTRACT
The first syntheses of functionalized sila-adamantanes via site-selective reactions are described. Mechanistic inquiry into the isomerization of sila-adamantane revealed new approaches for installing halides at the 2-position of the cluster. Meanwhile, isomerization via Lewis acid catalysts with non-nucleophilic counteranions provided access to sila-adamantane on the gram-scale, enabling us to discover strategies for substituting its 1-, 3-, 5-, and 7-positions with identical or distinct functional groups. Optical absorbance and density functional theory studies show that σ-withdrawing substituents at the 1-position strongly perturb optical absorbance in sila-adamantane, whereas substituents at the exocyclic and 2-position are optically inert. As silicon diamondoids are atomically precise models for silicon nanocrystals, our findings suggest that passivation at tertiary surface sites carries an outsized impact on the optical properties of surface-functionalized Si nanocrystals.
ABSTRACT
A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.
Subject(s)
Analgesics/chemistry , Benzimidazoles/chemistry , Central Nervous System/metabolism , Receptor, Cannabinoid, CB2/agonists , Analgesics/chemical synthesis , Analgesics/pharmacokinetics , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Microsomes, Liver/metabolism , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Nitriles/chemistry , Pyrazoles/chemistry , Reverse Transcriptase Inhibitors/chemistry , Acquired Immunodeficiency Syndrome/drug therapy , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line , Drug Resistance, Viral , HIV Reverse Transcriptase/metabolism , Humans , Microsomes, Liver/metabolism , Nitriles/chemical synthesis , Nitriles/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokineticsABSTRACT
The design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on a pyrazole template is described. These compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrazoles/chemistry , Reverse Transcriptase Inhibitors/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Drug Design , HIV Reverse Transcriptase/metabolism , Humans , Microsomes, Liver/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a-b, and Sulfonamide derivatives 11a-n proved to be potent agonists of the CB(2) receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.
