ABSTRACT
Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.
Subject(s)
Cannabinoid Receptor Agonists/therapeutic use , Chronic Pain/drug therapy , Piperazines/chemistry , Purines/chemistry , Receptor, Cannabinoid, CB2/agonists , Animals , Cannabinoid Receptor Agonists/chemistry , Cannabinoid Receptor Agonists/pharmacokinetics , Disease Models, Animal , Dogs , Half-Life , Humans , Microsomes, Liver/metabolism , Osteoarthritis/drug therapy , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Purines/pharmacokinetics , Purines/therapeutic use , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 µM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.
Subject(s)
Osteoarthritis/drug therapy , Purines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Animals , Dogs , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , HEK293 Cells , Humans , Male , Purines/pharmacokinetics , Purines/therapeutic use , Rats , Rats, Inbred Lew , Structure-Activity RelationshipABSTRACT
Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
Subject(s)
Chemistry, Organic/methods , Fluoxetine/chemical synthesis , Chemistry, Organic/instrumentation , Fluoxetine/chemistry , Halogens/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.
Subject(s)
Piperidines/chemistry , Protons , Spectrophotometry, Infrared , StereoisomerismABSTRACT
The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(-)-sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-sparteine-like diamine in such reactions. The (S,S)-diamine is a useful (+)-sparteine surrogate and was utilized in short syntheses of (-)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.
Subject(s)
Diamines/chemistry , Indolizines/chemical synthesis , Pyrrolidines/chemistry , Sparteine/chemistry , Cholecystokinin/antagonists & inhibitors , Diamines/chemical synthesis , Indolizines/chemistry , Proline/analogs & derivatives , Proline/chemical synthesis , Proline/pharmacology , StereoisomerismABSTRACT
The selective reduction of one of the three carboxyl groups of two chiral citric acid derivatives to the corresponding aldehydes, under Rosenmund conditions, are reported together with the application of these aldehydes to the syntheses of the ester side chains of some potently antileukemic Cephalotaxus alkaloids e.g. anhydroharringtonine.
Subject(s)
Alkaloids/chemistry , Antineoplastic Agents/chemistry , Cephalotaxus/chemistry , Citrates/chemistry , Esters/chemical synthesis , Antineoplastic Agents/chemical synthesis , Esters/chemistry , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
[reaction: see text] (+/-)-Cytisine has been synthesized in 19% overall yield via a six-step approach from commercially available materials. Key features of this new strategy are as follows: (i) initial construction of the bispidine core, (ii) lithiation-transmetalation-allylation of an N-Boc-bispidine, and (iii) a Pd/C-mediated dihydropyridone oxidation-N-debenzylation process.