Kevin D. McCormick

Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid

A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.

Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity.

A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.

Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists.

Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.

Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.

Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists.

A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.

Steroidal C-21 heteroaryl thioethers (Part 2): discovery of orally bioavailable selective glucocorticoid receptor modulators (dissociated steroids).

The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.

Role of α2-adrenoceptors in electrical field stimulation-induced contraction of pig nasal mucosa and pharmacologic characterization of a novel α2C-adrenoceptor agonist.

Background Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist. Methods Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension. The affinity and functional activity of compound B for α2C-adrenoceptors were determined by binding analysis and the ability of compound B to stimulate [35S]GTPγS binding to the receptors. Compound B was also tested in a postjunctional α2C-adrenoreceptor bioassay. Results EFS-induced contractions were partly blocked by the α2-adrenoreceptor antagonist yohimbine (41.1%) and the α2C-adrenoreceptor antagonist JP-1302 had no effect. The α2-adrenoreceptor agonist clonidine, but not compound B, exerted a significant blockade (70.6%). Compound B had high affinity (Ki = 18 nM), produced potent agonist (EC50 = 279 nM) and good efficacy (Emax = 73%) responses at the α2C-adrenoceptors, and displayed good functional agonist potency in the human saphenous vein α2C-adrenoreceptor bioassay (pD2 = 6.2). Conclusion (1) Neurogenic vasomotor contractility is largely regulated through an α-adrenergic mechanism; (2) pig nasal mucosa possesses post- and prejunctional α2-adrenoceptors; (3) the α2C-adrenoreceptor subtype does not seem to be involved; and (4) compound B is a novel, highly selective, and potent α2C-adrenoreceptor agonist.

Steroidal C-21 heteroaryl thioethers. Part 3: pregn-4-eno-[3,2-c]pyrazole fused A ring modified steroids as selective glucocorticoid receptor modulators (dissociated steroids).

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.