Ronald K. Russell

Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).

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.

Methylene amine substituted arylindenopyrimidines as potent adenosine A(2A)/A(1) antagonists.

A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinsons disease when dosed orally.

Two Step Synthesis of Substituted Indolo[1,2-a]-Quinoxalin-6-Ones

Abstract The reaction of indole-2-carboxylates with 2-fluoronitrobenzenes in 1-methyl-2-pyrrolidinone containing NaH affords the 1-(2-nitrophenyl)indole-2-carboxlyates 1. These compounds are reduced with iron in acetic acid to afford the indolo[1,2-a]quinoxalin-6(5H)-ones 2.

Optimization of arylindenopyrimidines as potent adenosine A(2A)/A(1) antagonists.

Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.

Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARδ agonists

Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.

Oxazolo[4, 5-b]pyridines. Regioselective metalation of the 2-diethylaminooxazolo[4, 5-b]pyridine system and formation of 7-substituted derivatives

Metalation of 2-diethylaminooxazolo[4, 5-b]pyridine with tert-butyllithium occurs regioselectively in the 7-position of the heterocycle and the fused 2-dialkylaminooxazolo group thus functions as an ortho-directing group in the bicyclic system. Reaction of the resulting 7-lithio intermediate with electrophiles provides access to a variety of 7-substituted derivatives.

Synthesis of a Novel Oxazolo[4,5-f][1,6]naphthyridine

Abstract 7-Azo-2-diethylaminooxazolo-[4,5-b]pyridine (1) is converted in 5 steps to the novel oxazolo[4,5-f][1,6]naphthyridine-6-oxo-7-carboxylic acid 6.

An Improved Non-chromatographic Scale-up Synthesis of a New 1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid as a Potent Bacterial Topoisomerase Inhibitor

7-[4-(2-Amino-1-chloroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4oxo-1,4-dihydroquinoline-3-carboxylic acid (10) is a potent bacterial topoisomerase inhibitor. In vitro, compound 10 is two-fold more potent than gemifloxacin when tested against ciprofloxacin-resistant Streptococcus pneumoniae clinical isolates (MIC90 = 1 μg/mL); it is also more potent than ciprofloxacin and gemifloxacin when tested against a collection of methicillin-resistant Staphylococcus aureus (MIC90 = 2 μg/mL) and coagulase-negative staphylococci isolates (MIC90 = 1 μg/mL).1,2 In order to prepare 100 g of compound 10 to facilitate in vivo investigation, it was decided to attempt to improve some of the steps of the original discovery medicinal chemistry (Discovery) route, an eight-step convergent synthesis with merely 6% overall yield of 10,1,2 and address the scale up issues that were identified in the following steps: first, the high exothermicity of the use of sodium hydride (NaH) to generate triethyl 2-chloro-2phosphonoacetate anion in the Horner-Wadsworth-Emmons reaction and its quenching (Step 1, Schemes 1), second, the reduction of ester 2 using DIBALH resulted in a 44% yield of alcohol 3 after chromatography (Step 2, Schemes 1), third, the product 4 of Mitsunobu reaction also required chromatographic purification (Step 3, Schemes 1), fourth the preparation of difluoroborate ester 7 required a large excess (11.9 equiv) of borontrifluoride etherate and extended reaction times (48–72 h), but gave only moderate to fair yields (50–78%) of 7 by precipitation of the crude product with diethyl ether