Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists.

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794).

Pharmacological characteristics of Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist: a potential therapy for stress urinary incontinence.

Objective: To describe the preclinical pharmacology of Ro 115-1240, a peripherally acting selective alpha1A/1L-adrenoceptor (AR) partial agonist, compared with the alpha1A/1L-AR full agonist amidephrine, as AR agonists have some utility in the treatment of stress urinary incontinence (SUI) but are limited by undesirable cardiovascular and central nervous system side-effects.

Results: In radioligand-binding studies Ro 115-1240 had greater affinity for alpha1A than for alpha1B and alpha1D subtypes. The potency and intrinsic activity of amidephrine and Ro 115-1240 relative to noradrenaline were determined in native and cell-based assays using human recombinant alpha1-ARs; they acted as selective alpha1A/1L-AR full and partial agonists, respectively.

Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat.

The marked analgesic efficacy of ketorolac in humans, relative to other nonsteroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to whether additional non-NSAID mechanism(s) contribute to its analgesic actions. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmacological properties in vivo and in vitro using the nonselective cyclooxygenase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as well as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writhing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema formation in rats; ID50 values = 0.

Stability of prostacyclin analogues: an unusual lack of reactivity in acid-catalyzed alkene hydration.

Prostacyclin analogue 5 undergoes specific acid-catalyzed hydration (kH+ = 1.9 x 10(-7)M-1 sec-1 at 25 degrees C) and a pH-independent oxidation reaction (k0 = 1.2 x 10(-10) sec-1 at 25 degrees C) above pH approximately 5.

Platelet aggregation inhibitory activity and vasodepressor activity of a series of bicyclo[3.2.0]hept-6-ylidene iminoxy alkanoic acids with modified lower side chains.

Prostacyclin analogues derived from modification of the lower side chain of the bicyclo[3.2.0]hept-6-ylidene iminoxyacetic acid (1) were studied in inhibition of in vitro and ex vivo platelet aggregation and in the spontaneously hypertensive rat.

Orally active prostacyclin-mimetic RS-93427: therapeutic potential in vascular occlusive disease associated with atherosclerosis.

RS-93427 is a potent, orally active prostacyclin-mimetic that is very rapidly absorbed but with generally long-lived actions in most species. It has antithrombotic, thrombolytic, and antivasospastic potential. Alone among several tested PGI-mimetics, it inhibits release of platelet mitogens more potently than its ability to inhibit aggregation.

Synthesis and platelet aggregation inhibition activity of a series of enantiomeric bicyclo[3.2.0]heptane-6-oximinoacetic acids (1).

Opening of racemic epoxide (3) with (3S)- or (3R)-dimethyl-3-(dimethyl-t-butylsilyloxy)oct-1-ynyl aluminum gave two regioisomers, which were separated chromatographically. The separated regioisomers, themselves mixtures of chromatographically inseparable diastereoisomers, were converted into their dicobalthexacarbonyl complexes, which were easily resolved and isolated by chromatography. The individual diastereoisomers were deprotected to give bicyclo[3.