ABSTRACT
In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.
Subject(s)
Interleukin-1 Receptor-Associated Kinases , Pyridones , Molecular Conformation , Pyridones/pharmacology , Structure-Activity RelationshipABSTRACT
The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.
ABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Benzamides/administration & dosage , Benzamides/chemistry , Dose-Response Relationship, Drug , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Benzofurans/chemistry , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzofurans/pharmacokinetics , Benzofurans/therapeutic use , Cell Line , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Pain/drug therapy , Rats , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity RelationshipABSTRACT
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
Subject(s)
Aminopyridines/therapeutic use , Brain/metabolism , Morpholines/therapeutic use , Pain/drug therapy , Receptor, Cannabinoid, CB2/agonists , Aminopyridines/pharmacokinetics , Animals , Aza Compounds , CHO Cells , Cell Line , Chronic Disease , Cricetinae , Cricetulus , Drug Discovery , Humans , Indoles , Morpholines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Subject(s)
Analgesics/chemical synthesis , Pyridines/chemical synthesis , Pyridines/therapeutic use , Receptor, Cannabinoid, CB2/agonists , Amides/chemical synthesis , Amides/pharmacology , Amides/therapeutic use , Analgesia/methods , Animals , Disease Models, Animal , Drug Discovery/methods , Inflammation , Pain/drug therapy , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
The first total synthesis of the natural nondimerizing o-quinol (+)-wasabidienone B1 was achieved from commercially available 1,3,5-trimethoxybenzene. The key dearomatizing transformation was efficiently accomplished via a hydroxylative phenol dearomatization reaction using the stabilized lambda(5)-iodane reagent IBX (SIBX). (+)-Wasabidienone B1 was then converted into its congener (-)-wasabidienone B0 via an improved thermally induced ring-contracting isomerization reaction.
Subject(s)
Iodobenzenes/chemistry , Lactones/chemical synthesis , Phenols/chemistry , Quinones/chemical synthesis , Catalysis , Hydroxylation , Indicators and Reagents/chemistry , IsomerismABSTRACT
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.