Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.     

Multilocus analysis of the evolutionary dynamics of rainforest bird populations in Southeast Asia

Sundaland has a dynamic geographic history because its landmasses were periodically interconnected when sea levels fell during glacial periods. Superimposed on this geographic dynamism were environmental changes related to climatic oscillations. To investigate how tropical taxa responded to such changes, we studied the divergence and demographic history of two co-distributed rainforest passerine species, Arachnothera longirostra and Malacocincla malaccensis. We sampled birds primarily from Borneo and the Malay Peninsula, which straddle the now-submerged Sunda shelf, and analysed multilocus DNA data with a variety of coalescent and gene genealogy methods. Cross-shelf divergence in both species occurred well before the last glacial maximum, i.e., before the most recent land connection. However, post-divergence gene flow occurred, and it was more pronounced in A. longirostra (a highly vagile nectarivore/insectivore) than in M. malaccensis (an understory insectivore). Despite current habitat continuity on Borneo, the population of M. malaccensis in northeastern Borneo is substantially divergent from that on the rest of the island. The NE population experienced dramatic demographic fluctuations, probably because of competition with the other population, which expanded from western Borneo after the mid-Pleistocene. In contrast, the Borneo population of A. longirostra has little structure and appears to have experienced demographic expansion 16 kya, long after it had diverged from the Malay Peninsula population (630-690 kya). Malay Peninsula populations of both species have remained relatively stable. Overall, the most recent glacial period was not the chief determinant of the evolutionary dynamics of our study species, and in this respect, they are different from temperate species.     

Molecular epidemiology of malaria prevalence and parasitaemia in a wild bird population

Avian malaria (Plasmodium spp.) and other blood parasitic infections of birds constitute increasingly popular model systems in ecological and evolutionary host-parasite studies. Field studies of these parasites commonly use two traits in hypothesis testing: infection status (or prevalence at the population level) and parasitaemia, yet the causes of variation in these traits remain poorly understood. Here, we use quantitative PCR to investigate fine-scale environmental and host predictors of malaria infection status and parasitaemia in a large 4-year data set from a well-characterized population of blue tits (Cyanistes caeruleus). We also examine the temporal dynamics of both traits within individuals. Both infection status and parasitaemia showed marked temporal and spatial variation within this population. However, spatiotemporal patterns of prevalence and parasitaemia were non-parallel, suggesting that different biological processes underpin variation in these two traits at this scale. Infection probability and parasitaemia both increased with host age, and parasitaemia was higher in individuals investing more in reproduction (those with larger clutch sizes). Several local environmental characteristics predicted parasitaemia, including food availability, altitude, and distance from the woodland edge. Although infection status and parasitaemia were somewhat repeatable within individuals, infections were clearly dynamic: patent infections frequently disappeared from the bloodstream, with up to 26% being lost between years, and parasitaemia also fluctuated within individuals across years in a pattern that mirrored annual population-level changes. Overall, these findings highlight the ecological complexity of avian malaria infections in natural populations, while providing valuable insight into the fundamental biology of this system that will increase its utility as a model host-parasite system.     

Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.     

The first enantioselective synthesis of the amavadin ligand and its complexation to vanadium

The ligand of the naturally occurring vanadium compound amavadin found in Amanita muscaria, (2S, 2'S)-N-hydroxyimino-2,2'-dipropionic acid (1), was synthesized stereoselectively in two steps with 43% overall yield. After complexation of this ligand to vanadyl acetate, amavadin was isolated in quantitative yield. Due to the chirality at vanadium amavadin consists of a mixture of delta and lambda diastereoisomers. Directly after its synthesis, the delta to lambda ratio of amavadin is 2.27 and it decreases to 0.80 after equilibrium has been reached. During this epimerization the optical rotation for V[(2S,2'S)-N-hydroxyimino-(2,2')-dipropionate]2 (=amavadin) changes from [alpha](D)25 = +36 degrees to +114.0 degrees (c = 0.5, H2O). For V[(2R,2'R)-N-hydroxyimino-(2,2')-dipropionate] the optical rotation changes from [alpha](D)25 = -36 degrees to -113.2 degrees (c = 0.5, H2O).     

Synthesis and bladder smooth muscle relaxing properties of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones

We have reported on the design, synthesis, and biological characterization of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (1), a novel, potent, and selective adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel opener with potential utility for the treatment of urge urinary incontinence (UUI). Excising the aniline-derived nitrogen atom of 1 or replacing it with an aralkyl group, led to bladder smooth muscle relaxant chemotypes 3 and 4, respectively. Prototype compounds in these series were found to produce significant increases in an iberiotoxin (IbTx)-sensitive hyperpolarizing current, thus suggesting that these relatively modest structural modifications resulted in a switch in the mechanism of action of these smooth muscle relaxants from K(ATP) channel openers to activators of the large-conductance Ca2+-activated potassium channel (BK(Ca)). We report herein the syntheses and biological evaluation of a series of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.     

Amino-substituted heterocycles as isosteres of trans-cinnamides: design and synthesis of heterocyclic biaryl sulfides as potent antagonists of LFA-1/ICAM-1 binding

2-Amino-4-phenyl pyridine and, to a lesser extent, 4-amino-6-phenyl pyrimidine, were established as isosteres of trans-cinnamide moiety. Applying this isosterism to previously reported p-arylthio cinnamides resulted in the identification of 4-amino-6-(p-arylthio)phenyl-pyrimidines and 2-amino-4-(p-arylthio)phenyl-pyridines as potent antagonists of LFA-1/ICAM-1 binding.     

Design, synthesis, and evaluation of proline based melanocortin receptor ligands

A series of proline based melanocortin ligands has been developed on the basis of initial piperazine leads by using a more conformationally rigid scaffold. A number of these novel ligands showed significant binding affinity for MC3 and MC4 receptors.