A- 770041 is a src-family selective lck inhibitor with greater than 90% inhibition of IL-2 in vivo at 8 h when dosed at ED90 in mice and rats. A-770041 is greater than 300-fold selective against fyn, the other src-family kinase involved in T-cell signaling. A-770041 exhibits >60-fold selectivity versus the src-family members src and fgr, and >8-fold versus lyn and hck. Selectivity against the receptor tyrosine kinases tie-2 and kdr was >340-fold. In the anti-CD3 stimulated human whole blood assay, A-770041 inhibited IL-2 production with an IC50 of 0.08 uM. In rats, a correlation of concanavalin A-induced serum IL-2 levels to A-770041 concentrations was observed. Inhibition of IL-2 production was shown to be dependent upon in vivo plasma concentration of A-770041 with an in vivo EC50 of 0.078 uM. A-770041 represents the most selective lck inhibitor described to date and represents an advance not only in the understanding of structural features important for src-family selectivity, but also in the potential arsenal for the treatment of immunological conditions, in particular transplant rejection.

A-967079 is a potent, selective, and orally bioavailable inhibitor of the TRPA1 channel, developed by developed by Abbott Laboratories for treatment pain disorder. A-967079 potently blocks human and rat TRPA1 channels. A-967079 is 1000-fold selective over other TRP channels and is 150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats. A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects.

A-987306 is a new histamine H(4) antagonist. A-987306 is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. A-987306 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 umol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain. A-987306 inhibited the scratching response (IC50 = 0.4 umoles/kg, i.p.) with (85%) inhibition seen at 30 umoles/kg, i.p. A-987306 is a potent and selective H4R antagonist with robust antipruritic activity and is a useful tool for further exploration of the role of H4R receptors in vivo.

A-943931 is a potent and selective H4R antagonist with high affinity at both human (Kis = 4.6 nM) and rat (Kis = 3.8 nM) receptors. A-943931 competitively and potently antagonizes rat H4R agonist-mediated responses in [35S]GTPγS binding assays (Kbs = 28 nM) and intracellular calcium mobilization at rat and human receptors (Kbs from 5-10 nM). When tested in vivo in a mouse model of clobenpropit (10 nM, i.d.) induced scratching, A-943931 inhibited the scratching response (IC50 = 26 umoles/kg, i.p.) with significant inhibition (69%) at the highest tested dose (30 umoles/kg, i.p.). A-943931 is a potent and selective H4R antagonist with robust antipruritic activity and is a useful tool for further exploration of the role of H4R receptors in vivo.

A-922500 is a potent, selective, and orally bioavailable DGAT-1 inhibitor. A-922500 confers weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depletes serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice. A-922500 (0.03, 0.3 and 3 mg/kg, p.o.) dose-dependently attenuates the maximal postprandial rise in serum triglyceride concentrations. DGAT-1 inhibition by A-922500 can be a novel therapeutic approach to the treatment of hypertriglyceridemia in humans.