Robert J. Chambers

Preparation of a novel series of phosphonate norstatine renin inhibitors

Abstract Replacement of the C-terminal isopropyl ester in the orally active norstatine renin inhibitor terlakiren (1) with dialkyl phosphonate groups provided a novel series of phosphorus norstatine inhibitors 2. Cyclic phosphonate 2f (IC50 = 0.6 nM) was prepared in an attempt to overcome apparent steric limitations of the phosphonate binding pocket and was found to be equipotent to ester 1. Like the ester norstatines, the phosphonate inhibitors preferred nonpolar P2 residues.

Regiospecific Carboalkoxylation of 2,5-Dibromopyridine

Abstract Carboalkoxylation of 2,5-dibromopyridine with carbon monoxide and an alcohol in the presence of palladium acetate and 1,1′-bis(diphenylphosphino) ferrocene (dppf) occurs regiospecifically to afford esters of 5-bromo-pyridine-2-carboxylic acid in good yield.

Biarylcarboxamide inhibitors of phosphodiesterase IV and tumor necrosis factor-α

Abstract Tumor necrosis factor-α (TNF-α) has been implicated as a key mediator in the progression of rheumatoid arthritis. Inhibitors of phosphodiesterase IV (PDE IV) have been shown to inhibit the production of TNF-α by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Our efforts in a series of biarylcarboxamides have led to the identification of 8j (CP-353,164) as a potent inhibitor of PDE IV and TNF-α production.

Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent α4β1 integrin antagonists

Abstract A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the α 4 β 1 integrin. The synthesis and SAR leading up to 3-[3-(1-{2-[3-methoxy-4-(3- o -tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid ( 22 ) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED 50 =2 μg/kg).

Development of new chromanol antagonists of leukotriene D4

By addressing the issues of potency and metabolism in 3, a new series of LTD4 antagonists represented by (+)-26 was developed which is equipotent to clinical LTD4 antagonists Zafirlukast (1) and Pranlukast (2).

Discovery of CP-199,330 and CP-199,331: Two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity

CP-199,330 (3) and CP-199,331 (4) are cysLT1 receptor antagonists that are equipotent to marketed cysLT1 receptor antagonists zafirlukast and pranlukast, show good pharmacokinetics in rats and monkeys, and are devoid of liver toxicity in monkeys as seen in CP-85,958 (1).

Synthesis and pharmacological profile of two novel heterocyclic chromanols, CP-80,798 and CP-85,958, as potent LTD4 receptor antagonists

Abstract The development of two novel LTD 4 receptor antagonists as clinical candidates for the treatment of asthma is described. The first generation compound, CP-80,798, was found to be a balanced 5-lipoxygenase inhibitor (5-LOI)/LTD 4 antagonist (LTD 4 -A), while the second generation compound, CP-85,958, is a selective LTD 4 antagonist.

Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists

A new series of cysLT1 receptor antagonists represented by CP-288,886 (7) and CP-265,298 (8) were developed which are equipotent to clinical cysLT1 receptor antagonists Zafirlukast (1) and Pranlukast (2).

An Improved Synthesis of 5-Fluorothiophene-2-Carboxylic Acid

Abstract A new and efficient route to 5-fluorothiophene-2-carboxylic acid 1 was secured in two steps and 62% yield overall.

The discovery of CP-96,021 and CP-96,486, balanced, combined, potent and orally active leukotriene D4 (LTD4)/platelet activating factor (PAF) receptor antagonists.

The combination of key structural pharmacophores found in known leukotriene D4 (LTD4) receptor antagonists with those of potent platelet activating factor (PAF) receptor antagonist UK-74,505 has led to the synthesis of hybrid compounds CP-96,021 and CP-96,486. These compounds represent the first known balanced, combined and orally active LTD4/PAF receptor antagonists.