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Evolution of a synthetic process to prepare ABBV-105, a Bruton's tyrosine kinase (BTK)-inhibitor, on multikilogram scale is described. The first-generation route utilized chiral resolution of the penultimate intermediate (7). Either Bartoli or Leimgruber–Batcho indole synthesis was used to prepare the key intermediate, indole boronate ester (23). As the demand for the API increased, the first-generation route was found to be low-yielding and expensive. It required column chromatography, had multiple alerting structures from the mutagenic impurity assessment, and suffered from lack of robustness. In the second-generation route a novel Ru-catalyzed asymmetric hydrogenation of 1,2,5,6-tetrahydropyridine (21) was developed to establish the stereocenter. Compound 21 was accessed via Suzuki coupling of 23, prepared by Friedel–Crafts acylation, with vinyl bromide (24) in the presence of very low loading of a Pd catalyst (0.15 mol % Pd). Finally, the penultimate intermediate (7) was coupled with acryloyl chloride using an impinging jet to prepare the API. Detailed kinetic and mechanistic work was conducted to control the persistent impurities formed in the API step. The second-generation route was robust, chromatography-free and high-yielding with low mutagenic liability.
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C–O bond formation as key steps.
Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.
Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.
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