AM-095 free base

AM095 is a novel, potent and orally bioavailable antagonist of lysophosphatidic acid type 1 receptor (LPA1) with IC50 values of 0.73 and 0.98 μM for mouse or recombinant human LPA1, respectively [1].

In vitro, AM095 has shown to inhibit LPA1-induced chemotaxis of both mouse LPA1/CHO cells and human A2058 melanoma cells with IC50 values of 0.78 μM and 0.23μM [1].

In vivo, AM095 could dose-dependently block LPA-induced histamine release with an ED50 value of 8.3 mg/kg in mice. Additionally, AM095 has been revealed to remarkably reduce the BALF collagen and protein with an ED50 value of 10 mg/kg in lungs. AM095 has also shown to decrease both macrophage and lymphocyte infiltration induced by bleomycin in mice [1].

References:
[1] Swaney JS1, Chapman C, Correa LD, Stebbins KJ, Broadhead AR, Bain G, Santini AM, Darlington J, King CD, Baccei CS, Lee C, Parr TA, Roppe JR, Seiders TJ, Ziff J, Prasit P, Hutchinson JH, Evans JF, Lorrain DS. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.

Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst-, Base-, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanides.[Pubmed:28362091]

J Org Chem. 2017 Apr 21;82(8):4444-4448.

An efficient catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN has been developed under mild conditions. This strategy provides an elusive and rapid access to a wide range of cyano-containing phenanthridine derivatives in good yields via a one-pot alkylation/cyclization radical-cascade process. The mild reaction conditions together with no need of any catalyst, base, or oxidant make this protocol environmentally benign and practical.

Stabilization and Structure of the cis Tautomer of a Free-Base Porphyrin.[Pubmed:28370984]

Angew Chem Int Ed Engl. 2017 Aug 14;56(34):10088-10092.

Single-crystal X-ray analysis of the beta-heptakis(trifluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H2 [(CF3 )7 TpFPP], has revealed the first example of a stable cis tautomer of a free-base porphyrin, the long-postulated intermediate of porphyrin tautomerism. The stability of the unique molecule appears to reflect a dual origin: a strongly saddled porphyrin skeleton, which alleviates electrostatic repulsion between the two NH protons, and two polarization-enhanced, transannular N-HO-HN hydrogen bond chains, each involving a molecule of water. DFT calculations suggest that the observed tautomer has a lower energy than the alternative, doubly hydrated trans tautomer by some 8.3 kcal mol(-1) . A fascinating prospect thus exists that H2 [(CF3 )7 TpFPP]2 H2 O and cognate structures may act as supramolecular synthons, which, given their chirality, may even be amenable to resolution into optically pure enantiomers.

The Laparoscopically Harvested Omental Free Flap: A Compelling Option for Craniofacial and Cranial Base Reconstruction.[Pubmed:28321385]

J Neurol Surg B Skull Base. 2017 Apr;78(2):191-196.

Background Management of craniofacial and cranial base tumors is a challenge due to the anatomic intricacies associated with the calvarium, the pathological diversity of lesions that present, and the potential complications. Clinical outcomes in laparoscopically harvested omentum free flaps for cranial base and craniofacial reconstruction are presented in this paper, in the largest case series to date. Methods A retrospective single-center experience for over 10 years with laparoscopically harvested omentum flaps used to reconstruct craniofacial and cranial base defects. Results A total of 13 patients underwent craniofacial or cranial base reconstruction using laparoscopically harvested omentum free flaps. The mean patient age was 48 years. The anterior skull base represented the most common site of reconstruction. A total of 12 of the flaps survived (92%), with one flap failure due to infection. All patients demonstrated satisfactory aesthetic and functional outcomes. There were no perioperative or intra-abdominal complications. Conclusions The laparoscopically harvested omentum free flap is a safe and effective tool in the armamentarium of the reconstructive surgeon. It is the ideal option to treat complex, three-dimensional subcutaneous defects, such as those encountered in craniofacial and cranial base reconstruction. Its unique angiogenic and immunologic capacity makes it an excellent flap for the previously irradiated and/or infected wound bed.

Chiral Tertiary Sulfonium Salts as Effective Catalysts for Asymmetric Base-Free Neutral Phase-Transfer Reactions.[Pubmed:28371093]

Angew Chem Int Ed Engl. 2017 Apr 18;56(17):4819-4823.

Although chiral quaternary ammonium and phosphonium salts are commonly used for asymmetric organocatalysis, the catalytic ability of chiral tertiary sulfonium salts has yet to be demonstrated in asymmetric synthesis. Herein, we show that chiral bifunctional trialkylsulfonium salts catalyze highly enantioselective conjugate additions of 3-substituted oxindoles to maleimides under base-free neutral phase-transfer conditions.

AM095 (free acid) is a potent LPA1 receptor antagonist with IC50 values of 0.98 and 0.73 μM for recombinant human or mouse LPA1 respectively.

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