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fasted, high-fat fed rats in an oGTT. The inhibitors represented by compounds
8-12 provided useful insights for the design of DPP4 inhibitors at BMS.
At the initiation of the program, there were still many unknown factors
related to the pharmacology and safety of DPP4 inhibition. It was clear from
earlier work that Fischer 344 rats possessing a naturally occurring loss-of-
function mutation of the DPP4 gene were healthy, viable, and free of serious
immunological complications.
37
It was later shown that these rats also exhib-
ited a favorable metabolic phenotype on a high-fat diet and demonstrated
improved glucose tolerance and GLP-1 secretion.
38
Thus, complete ablation of
DPP4 did not appear to represent a serious safety concern in rats, but rather the
Fischer rat provided support for the concept that inhibition of DPP4 could be
both safe and ecacious. Others questions still remained. Was high selectivity
for DPP4 versus other related peptidases (e.g. DPP8, DPP9, FAP, etc.) an
absolute requirement for this target? Would inhibition of DPP4 potentiate
other endogenous peptides, leading to unintended deleterious (or beneficial)
consequences? Would potentiating endogenous GLP-1 (versus exogenous
administration) be sucient to affect a robust anti-diabetic response in
humans? Finally, what potential mechanism-based toxicological effects, if any,
would be seen upon chronic administration of a DPP4 inhibitor?
In light of limited literature in the field, and with no reports of a compound
having advanced to clinical trials, these questions would ultimately need to be
addressed during the execution of our discovery and subsequent clinical
development programs. Despite the unknowns, the positive aspects of this
target were numerous. Potent small-molecule inhibitors with systemic exposure
upon oral dosing were known. Although limited, DPP4 inhibitors had
demonstrated pharmacodynamic ecacy in genetic animal models of type 2
diabetes in preliminary pharmacological studies. Preclinical proof-of-concept
for the anti-diabetic actions of GLP-1 was already established and suggested a
low potential for hypoglycemia. In vitro assays and several in vivo models were
already described in the literature, enabling rapid program initiation. It was
against this backdrop that significant medicinal chemistry and biology
resources at BMS were deployed on this newly emerging target in the early
months of 1999.
1.5 Design of BMS's DPP4 Medicinal Chemistry
Program
Given the attractiveness of DPP4 as a therapeutic target, it was anticipated that
this field would soon become highly competitive, and we therefore sought to
accelerate the program. High-throughput screening (HTS), routinely a key
component of drug discovery programs, was deemed as too time consuming to
rapidly afford a chemical starting point. Thus, we decided to initially adopt a
design optimization approach, improving upon the leads reported by the
Probiodrug, Ferring, and Novartis research groups; HTS would later be used
to provide leads for a second-generation effort. From a potency perspective, the
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