Brian C. Shook

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477

Adenosine A2A Receptor Antagonists and Parkinson’s Disease

This Review summarizes and updates the work on adenosine A(2A) receptor antagonists for Parkinsons disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinsons disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A(2A) antagonists, but a few approaches to dual A(2A)/A(1) antagonists will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials.

In vivo characterization of a dual adenosine A2A/A1 receptor antagonist in animal models of Parkinson's disease.

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinsons disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinsons disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

Design and Characterization of Optimized Adenosine A2A/A1 Receptor Antagonists for the Treatment of Parkinson's Disease

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinsons disease is described. Compound 1 was previously reported as a potential treatment for Parkinsons disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinsons disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

Overcoming the Genotoxicity of a Pyrrolidine Substituted Arylindenopyrimidine As a Potent Dual Adenosine A2A/A1 Antagonist by Minimizing Bioactivation to an Iminium Ion Reactive Intermediate

2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno[1,2-d]pyrimidin-5-one (1) is a novel and potent selective dual A(2A)/A(1) adenosine receptor antagonist from the arylindenopyrimidine series that was determined to be genotoxic in both the Ames and Mouse Lymphoma L5178Y assays only following metabolic activation. Compound 1 was identified as a frame-shift mutagen in Salmonella typhimurium tester strain TA1537 as indicated by a significant dose-dependent increase in revertant colonies as compared to the vehicle control. The metabolic activation-dependent irreversible covalent binding of radioactivity to DNA, recovery of 1 and its enamine metabolite from acid hydrolysis of covalently modified DNA, and protection of covalent binding to DNA by both cyanide ion and methoxylamine suggest that the frame-shift mutation in TA1537 strain involved covalent binding instead of simple intercalation to DNA. Compound 1 was bioactivated to endocyclic iminium ion, aldehyde, epoxide, and α,β-unsaturated keto reactive intermediates from the detection of cyano, oxime, and glutathione conjugates by data-dependent high resolution accurate mass measurements. Collision-induced dissociation of these conjugates provided evidence for bioactivation of the pyrrolidine ring of 1. The epoxide and α,β-unsaturated keto reactive intermediates were unlikely to cause the genotoxicity of 1 because the formation of their glutathione adducts did not ameliorate the binding of compound related material to DNA. Instead, the endocyclic iminium ions and amino aldehydes were likely candidates responsible for genotoxicity based on, first, the protection afforded by both cyanide ion and methoxylamine, which reduced the potential to form covalent adducts with DNA, and, second, analogues of 1 designed with low probability to form these reactive intermediates were not genotoxic. It was concluded that 1 also had the potential to be mutagenic in humans based on observing the endocyclic iminium ion following incubation with a human liver S9 preparation and the commensurate detection of DNA adducts. An understanding of this genotoxicity mechanism supported an evidence-based approach to selectively modify the structure of 1 which resulted in analogues being synthesized that were devoid of a genotoxic liability. In addition, potency and selectivity against both adenosine A(2A) and A(1) receptors were maintained.

JNJ-40255293, a Novel Adenosine A2A/A1 Antagonist with Efficacy in Preclinical Models of Parkinson’s Disease

Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinsons disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50s of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinsons disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.

β-Siloxy unsaturated nitriles: stereodivergent cyclizations to cis- and trans-decalins

Abstract Nitrile and enolate anions exhibit divergent intramolecular cyclization stereoselectivities. Enolates cyclize to cis-decalones, whereas nitrile anions are predisposed to pyramidalize, cyclizing instead through a less-congested conformation to trans-decalins. Conjugation of nitrile anions with adjacent sp2 centers prevents pyramidalization, and redirects cyclization through a planar-delocalized anion to cis-decalins. Collectively these cyclizations allow conversion of a single β-siloxynitrile to either cis- or trans-decalins that are ideally suited for elaboration into terpenoid natural products.

α,β-Unsaturated nitriles: preparative MgO elimination

Abstract Double deprotonation of β-hydroxynitriles with MeMgCl (2.1 equiv.) generates a dianion that ejects MgO to provide the corresponding α,β-unsaturated nitriles. Structurally diverse β-hydroxynitriles readily eliminate MgO providing an expedient route to highly substituted α,β-unsaturated nitriles.

Strategies for Enhancing Oral Bioavailability and Brain Penetration

Publisher Summary One of the most time-consuming portions of a medicinal chemistry program is attempting to increase the bioavailability of a lead compound. There are several strategies available, depending on what the target organ is. This chapter summarizes some recent examples of structural modifications that have increased the bioavailability of compounds. It deals with efforts to increase oral bioavailability and describes examples in which structural modifications lead to increases in brain penetration. Altering the basicity of a molecule can increase bioavailability. This is a common strategy used to increase the brain penetration of a compound. There are a number of strategies routinely used to try to increase oral bioavailability of a compound. In terms of brain bioavailability, it is common to focus first on log P calculations and minimization of molecular weight to obtain increased brain bioavailabilities.