Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting ß2-adrenoceptor agonist.

The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing α-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.

Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate.

The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.

The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.

A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential.

The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.