Small molecule glucagon receptor antagonists: an updated patent review (2015-2019).

INTRODUCTION: The peptide hormone glucagon acts as a counterregulatory response to hypoglycemia and as a key driver in the development of all forms of diabetes. Thus, inhibition of glucagon action, including through antagonism of the glucagon receptor by small molecule therapeutics, has been explored in clinical settings as a means to achieve glycemic control in patients with type 2 diabetes mellitus and mitigate associated comorbidities. AREAS COVERED: This review covers patent applications concerning small molecule glucagon receptor antagonists (GRAs) published between 2015 and 2019. With the exception of the cholesterol absorption inhibitor-GRA combination, patents, or applications pertaining to combination therapies or method of treatment were excluded. In addition, a discussion on findings from clinical trials is included. EXPERT OPINION: An evident trend toward declining discovery efforts in GRAs was observed. With respect to the structural novelty, most applications contain compounds broadly similar to earlier chemical matter. Based on findings from clinical trials, while GRAs are highly effective in lowering hemoglobin A1c (HbA1c) levels, key safety issues (cholesterol elevation, aminotransferase elevation, blood pressure effects) remain the primary hurdle for the field.

Selective N7 Alkylation of 7-Azaindazoles.

A general and mild procedure for alkylation of 7-azaindazoles at the N7 position using alkyl halides in butanone is reported, which requires no additives such as acids or bases. The scope of the reaction regarding substituents on 7-azaindazoles and the alkyl electrophiles is presented.

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

Enantioselective total syntheses of plectosphaeroic acids B and C.

Evolution of the synthetic strategy that culminated in the first total syntheses of the structurally unique plectosphaeroic acids B (2) and C (3) is described. The successful enantioselective route to (+)-2 and (+)-3 proceeds in 6 and 11 steps from the known hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione 39, which in turn is available in enantiomerically pure form by chemical synthesis. The central challenge in this synthesis endeavor was uniting the hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione and cinnabarinic acid fragments of these marine alkaloids. Critical for achieving this successful C-N bond formation was the use of an iodocinnabarinic acid diester in which the amino group was masked with two Boc substituents, a Cu(I) carboxylate complex and the weak base KOAc. The highly congested C-N bond generated in this coupling, in conjunction with the delicate nature of the densely functionalized coupling partners, provided a striking testament to the power of modern copper-mediated amination methods. Two approaches, one stereoselective, for introducing the methylthio substituents of (+)-plectosphaeroic acid B were developed. The epitrisulfide ring of (+)-plectosphaeroic acid C was formed by ring expansion of an epidisulfide precursor.

Enantioselective total synthesis of plectosphaeroic acid B.

The first total synthesis of a member of the plectosphaeroic acid family of fungal natural products is reported. Key steps include the late-stage formation of the hindered N6-C9" bond and stereoselective introduction of the two methylthio substituents.

Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors.

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11) in 10 steps and 11% overall yield from isatin is reported. In addition, the epipolythiodioxopiperazine (ETP) natural product (+)-gliocladine C (6) has been prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of 6 constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.

Tricyclic HIV integrase inhibitors V. SAR studies on the benzyl moiety.

SAR studies on the para-fluorobenzyl moiety of tricyclic HIV integrase inhibitors are discussed and lead compounds with potency and PK properties comparable to raltegravir were identified.

Tricyclic HIV integrase inhibitors: VI. SAR studies of 'benzyl flipped' C3-substituted pyrroloquinolines.

A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the 'halobenzyl tail' at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC(50) and t(1/2) in animal PK studies.

Tricyclic HIV integrase inhibitors: potent and orally bioavailable C5-aza analogs.

A series of C5-aza tricyclic HIV integrase inhibitors was prepared. A highly potent and orally bioavailable compound (compound 9) was identified and selected for development.

Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors.

A novel class of tri-cyclic HIV integrase inhibitors were designed based on conformational analysis of 1,6-naphthyridine carboxamide compound L-870810 and docking the designed inhibitor into the active site of our integrase enzyme model. The efficient syntheses of pyrroloquinoline tri-cyclic analogs are described. The SAR studies resulted in the identification of a lead compound that is more potent and more soluble than L-870810.

Effect of substitution on novel tricyclic HIV-1 integrase inhibitors.

A series of novel tricyclic inhibitors of HIV-1 integrase enzyme was prepared. The effect of substitution at C-6 of the 9-hydroxy-6,7-dihydropyrrolo[3,4-g]quinolin-8-one compounds was studied in vitro. Inhibitors with small side chains at C-6 were generally well tolerated by the enzyme, and the physicochemical properties of the inhibitors were improved by substitution of a small alkyl group at this position. A second series of analogs bearing a sulfamate at the C-5 position with various C-6 substituents were prepared to explore the interplay between the two groups. The SAR of the two classes are not parallel; modification at C-5 impacts the effect of substitutions at C-6.