Chafiq Hamdouchi

3-(4-Chloro-2-Morpholin-4-yl-Thiazol-5-yl)-8-(1-Ethylpropyl)-2,6-Dimethyl-Imidazo[1,2-b]Pyridazine: A Novel Brain-Penetrant, Orally Available Corticotropin-Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism

We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of ∼1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.

Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors

BackgroundAnimal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.ResultsFocal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.ConclusionThese results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

On the reaction of chiral sulfinimines with sulfur ylides: a novel route to the asymmetric aziridination

Abstract The reaction of optically pure N-sulfinyl phenylimine with dimethyloxosulfonium methylide ( A ) and dimethylsulfonium methylide ( B ) yields a mixture of N-sulfinylaziridines, epimers at C-2, which are easily separated. The stereochemical outcome of this aziridination was shown to be dependent on the nature of the methylene transfer reagent. The elimination of the sulfinyl group occurs under mild conditions, leading to optically pure phenyl aziridines.

A new approach to the synthesis of 2-aminoimidazo[1,2-a]pyridine derivatives through microwave-assisted N-alkylation of 2-halopyridines

Abstract A microwave (focused waves) assisted N-alkylation of 2-halopyridines provides a convenient entry to 2-amino-imidazo[1,2-a]pyridine derivatives after reaction of the alkylated substrates with cyanamide under basic conditions.

A novel application of the Ullmann coupling reaction for the alkylsulfenylation of 2-amino-imidazo[1,2-a]pyridine

Abstract The Ullmann coupling reaction between the 2-trifluoroacetamido-3-iodo-6-benzoylimidazo[1,2-a]pyridine and dialkyldisulfides (Me, iPr) mediated by copper bronze in pyridine, resulted in a novel and highly efficient method for the incorporation of alkylthiol groups at C-3 of this type of heterocyclic system.

Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: The effect of acyl groups at 3-position

Various 2-amino-3-acyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]-imidazo[1 ,2-a]pyridines, structurally related to Enviroxime were prepared to determine the effect of acyl groups on the anti-rhinoviral activity. A short and efficient means for the construction of the imidazo nucleus as well as biological evaluation of the final compounds are disclosed.

Regioselective synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines

A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines 3 is described. A halogen–metal exchange study on building block 1 showed that use of i-propyl magnesium chloride is most effective for chemoselective functionalization at position 6. Further regiospecific metalation at position 3, followed by quenching with different electrophiles, afforded target compounds.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470)

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

A NEW STEREOCONTROLLED ENTRY INTO THE ANTHRACYCLINONE FAMILIES. PART 1 : SYNTHESIS OF BICYCLIC PRECURSORS OF 4-DEMETHOXY-7-DEOXY-DERIVATIVES

Abstract A new and versatile strategy to obtain enantiomerically pure bicyclic precursors of compounds belonging to different anthracyclinone families is reported. Completely stereoselective hydrocyanation of ( R )-4-(2,5-dimethoxyphenyl)-1- p -tolylsulfinyl-2-butanone and further intramolecular capture of the Pummerer intermediate generated from the resulting sulfinylcyanohydrin are the key steps to obtain the bicyclic nitrile 2 with the proper configuration and functionality at C-9.

New one-step process for the synthesis of functionalized 1,6-dioxaspiro[4,5]decanes

Abstract β-Phenylsulfonyl dihydrofurans 1 were readily prepared by reduction of α-phenylsulfonyl-γ-lactones with DIBAL-H, followed by dehydration with MsCl-Et3N. Dihydrofurans 1 were deprotonated with n-BuLi and the resulting α-lithiated carbanion reacted with a wide variety of electrophiles. Particularly interesting is its reaction with γ-lactones because affords 1,6-dioxaspiro[4,5]decanes in good yields in one-step procedure. This new method of synthesis of spiroketals, in non-acid conditions, is thermodynamically controlled and occurs with high stereoselectivity at C-4, C-5 and C-7, but not at C-2.