Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.

The development of asymmetric Morita-Baylis-Hillman (MBH) reactions has evolved dramatically over the past few years, parallel to the emerging concept of bifunctional organocatalysis. Whereas organocatalysis is starting to compete with metal-based catalysis in several important organic transformations, the MBH reaction belongs to a group of prototypical reactions in which organocatalysts already display superiority over their metal-based counterparts. This Minireview summarizes recent mechanistic insights and advances in the design and synthesis of small organic molecules for enantioselective MBH and aza-MBH reactions.

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.

Asymmetrische Morita‐Baylis‐Hillman(MBH)‐Reaktionen haben sich in den letzten Jahren parallel zum Konzept der difunktionellen Organokatalyse rasant weiterentwickelt. Während die Organokatalyse im Allgemeinen erst beginnt, bei einer Reihe wichtiger organischer Umwandlungen mit der Metallkatalyse zu konkurrieren, zählt die MBH‐Reaktion zu einer Gruppe prototypischer Reaktionen, für die organische Katalysatoren ihren metallhaltigen Analoga bereits jetzt überlegen sind. Dieser Kurzaufsatz gibt einen Überblick über neue mechanistische Erkenntnisse und Fortschritte bei der Synthese von niedermolekularen organischen Verbindungen für enantioselektive MBH‐ und Aza‐MBH‐Reaktionen.

Oxazine derivatives R 0595Synthesis of α-Isocyano-α-alkyl (aryl)acetamides and Their Use in the Multicomponent Synthesis of 5-Aminooxazole, Pyrrolo[3,4-b]pyridin-5-one and 4,5,6,7-Tetrahydrofuro[2,3-c]pyridine. -With the isonitrile (V) in hand, novel multicomponent reactions to prepare 5-aminooxazoles, pyrrolopyridinones, and tetrahydrofuropyridines are developed. -(FAYOL, A.; HOUSSEMAN, C.; SUN, X.; JANVIER, P.; BIENAYME, H.; ZHU*, J.; Synthesis 2005, 1, 161-165; Inst. Chim. Subst. Nat., CNRS, F-91198 Gif-sur-Yvette, Fr.; Eng.) -Jannicke 20-161

Alkylation of a-isocyano acetamide (2) with alkyl halide in MeCN at 0°C in the presence of cesium hydroxide afforded the mono-alkylated product 1 in good to excellent yield.Functionalized isonitriles have found wide application in the syntheses of heterocycles. 1-3 Although less popular than a-isocyano acetate 4 and tosylmethyl isocyanide (TosMIC), 5 a-substituted a-isocyano acetamides (1) 6 have recently been developed into a powerful bifunctional substrate for the multicomponent syntheses of heterocycles 7,8 and macrocycles. 9 Indeed, the reactivity profile of a-isocyano acetamide (1) was found to be rather different from that of a-isocyano acetate under mild basic or acidic conditions. Compound 1 has previously been synthesized from the corresponding amino acid in three conventional steps via a sequence of N-formylation, amidation of carboxylic acid and dehydration. 10 Although the sequence is high-yielding for the synthesis of each individual compound, its limitation in the high-throughput synthesis of a diverse collection of this class of isonitriles is self-evident. Consequently, we were interested in developing a more efficient synthesis of 1 in order to fully exploit its synthetic potential.Benzylation of a-isocyano acetamide (2) providing the corresponding a,a-bisalkylated derivative has been developed by Matsumoto in 1977. 11 To the best of our knowledge, this is the only report found in the open literature dealing with the alkylation of 2 and indeed conditions allowing the monoalkylation of (2) remained unknown. Similarly, alkylation of methyl a-isocyano acetate (3) afforded the corresponding bisalkylated product even with a substoichiometric amount of alkylating agent. 12, 13 We report herein that monoalkylation of (2) can be realized under appropriate conditions to afford a-substituted a-isocyano acetamides (1) in good to excellent yield (Scheme 1).a-Isocyano acetamides (2) were synthesized as shown in Scheme 2. Stirring a methanol solution of a-isocyano acetate (3) with morpholine and pyrrolidine afforded the corresponding amides 2a and 2b in yields of 85% and 77%, respectively (Scheme 2, a). On the other hand, EDCI mediated coupling of the potassium salt of a-isocyano acetic acid 14 with diethylamine provided the amide 2c in 49% yield. The Weinreb amide 2d was similarly prepared in 69% yield (Scheme 2, b). 15The benzylation of morpholino a-isocyano acetamide 2a with benzyl bromide (6a) was examined as a model reaction by varying the bases, the reaction temperatures, and the solvents (Table 1). As is seen, no reaction occurred when NaOH, DBU and Cs 2 CO 3 were used as bases regardless of the nature of solvents used (THF, CH 2 Cl 2 , biphasic solution, entries 1-4). In accord with Mastumoto's observation, performing the alkylation in THF in the presence of sodium hydride afforded 1a in only 10% yield (entry 5). The dibenzylated compound was produced in 30% yield under these conditions. Gratifyingly, cesium hydroxide was found to be able to promote the desired monoalkylation in a variety of solvents ...

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