Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the ®rst small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an a nity (K i ) for human CGRP receptors of 14.4+6.3 (n=4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 mg kg 71 (i.v.) inhibited the e ects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood¯ow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.

No abstract

1 The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N- [[4-(aminocarbonylaminomethyl)phenyl]methyl]-N 2 -(diphenylacetyl)-argininamide tri¯uoroacetate) has been synthesized and was examined for its subtype selectivity, its in vitro antagonistic properties and its food intake inhibitory properties. 2 BIBO 3304 displayed subnanomolar anity for both the human and the rat Y1 receptor (IC 50 values 0.38+0.06 nM and 0.72+0.42 nM, respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low anity for both the human and rat Y1 receptor subtype (IC 50 41000 nM). BIBO 3304 showed low anity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC 50 values 41000 nM). 3 30 mg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 mg NPY as well as the hyperphagia induced by a 24 h fast implying a role for Y1 receptors in NPY mediated feeding. The inactive enantiomer had no eect. 4 BIBO 3304 inhibits neither the galanin nor the noradrenaline induced orexigenic response, but it blocked feeding behaviour elicited by both [Leu 31 , Pro 34 ]NPY and NPY (3 ± 36) suggesting an interplay between dierent NPY receptor subtypes in feeding behavior. 5 The present study reveals that BIBO 3304 is a subtype selective nonpeptide antagonist with subnanomolar anity for the Y1 receptor subtype that signi®cantly inhibits food intake induced by application of NPY or by fasting.

No abstract

No abstract

Novel pyrido[2,3-b][1,4]benzodiazepinones (I), pyrido[2,3-b][1,5]benzodiazepinones (II), and dipyrido[3,2-b:2',3'-e][1,4]diazepinones (III) were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in vitro at concentrations as low as 35 nM. In all three series, small substituents (e.g., methyl, ethyl, acetyl) are preferred at the lactam nitrogen, whereas slightly larger alkyl moieties (e.g., ethyl, cyclopropyl) are favored at the other (N-11) diazepinone nitrogen. In general, lipophilic substituents are preferred on the A ring, whereas substitution on the C ring generally reduces potency relative to the corresponding compounds with no substituents on the aromatic rings. Maximum potency is achieved with methyl substitution at the position ortho to the lactam nitrogen atom; however, in this case an unsubstituted lactam nitrogen is preferred. Additional substituents on the A ring can be readily tolerated. The dipyridodiazepinone derivative 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-one (96, nevirapine) is a potent (IC50 = 84 nM) and and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase, and has been chosen for clinical evaluation.

No abstract

Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.