Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778)

Abstract

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.

Synthesis of New Pyrrolo Heterocycles (I): Novel Synthesis of Pyrano[2,3‐c]pyrrole, Isoindoline, Pyrrolo[3,4‐b]pyridine, and Pyrrolo[3,4‐d]pyrimidine Derivatives

“…The synthesis and biological activities of the pyrrolo[3,4‐ b ]pyridines have been reported . Early, 4‐arylmethylene‐1‐substituted‐2,3‐dioxopyrrolidines were condensed with ethyl β‐aminocrotonate or 4‐aminopent‐3‐en‐2‐one to give adducts, which could be dehydrogenated to the corresponding pyrrolo[3,4‐ b ]pyridines .…”

Synthesis of Polyheterocyclic Dimers Containing Restricted and Constrained Peptidomimetics via IMCR-Based Domino/Double CuAAC Click Strategy

“…In addition, the synthesis of molecules containing restricted and constrained PHPs via IMCR, followed by a domino process and subsequent CuAAC The pyrrolo [3,4-b]pyridin-5-one is an important fragment for building conformationally constrained peptidomimetics. Compounds incorporating this fused heterocycle exhibit a wide range of biological activities including anti-diabetic agents [16], anticancer, analgesic, and therapeutic agents for central nervous system-related diseases such as Alzheimer's, epilepsy, and schizophrenia [17][18][19][20]. Furthermore, Wager et al reported the synthesis of their analogs with brain-selective radioligand properties [21].…”

MW-Assisted Synthesis of Eight New 6-Nitrilmethyl Pyrrolo[3,4-b]pyridin-5-Ones via a Domino Process: aza Diels–Alder/N-Acylation/Aromatization

“…The fused-type polyheterocyclic pyrrolo [3,4-b]pyridin-5-one system 1 is the structural core of various synthetic products showing interesting biological properties, such as the antiepileptic 2 [1] and the antihypoglycemic 3 [2] agents. Besides, the polyheterocyclic framework 1 is considered as a privileged aza analogue of the isoindolin-1-one system 4 [3].…”

“…Thus, the aim of this communication is to describe an efficient MW-assisted synthesis of eight new 6-nitrilmethyl-pyrrolo [3,4-b]pyridin-5-ones 8a-h via a domino process: aza Diels-Alder/Nacylation/aromatization (dehydration-decarboxylation) from their corresponding 2-aminonitrileoxazoles and maleic anhydride. Most of the reported methods to assemble pyrrolo [3,4-b]pyridin-5one based architectures involve multistep strategies as well as the use of harsh conditions-see for example the synthetic methodology reported by Devasthale et al [2]. However, various multicomponent reaction (MCR)-based synthetic strategies toward series of novel pyrrolo [3,4b]pyridin-5-one-containing polyheterocycles have been reported in the last decade by us [7][8][9][10][11][12][13][14] as an integral part of our ongoing research program.…”