Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have ...developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC
50: 91–650
nM) against renin while remaining ‘Rule-of-five’ compliant.
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC
50: 91–650
nM) against renin while remaining ‘Rule-of-five’ compliant.
Herein, we report the discovery of novel, proline‐based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of ...1‐(4‐amino‐3‐fluoro‐phenyl)‐1H‐pyridin‐2‐one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
With the intent to improve upon the projected human half-life of the previously disclosed Factor Xa inhibitor
5, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored. This work ...led to the discovery of
26, a selective, orally bioavailable, and efficacious Factor Xa inhibitor.
Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus
5 (projected human
t
1/2
=
6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to
5. Reported herein is the discovery of
26, containing a (2
R,4
S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human
t
1/2
=
23 h).
A series of ketopiperazine-based renin inhibitors designed to interact in the S
3 sub-pocket of the renin protein were evaluated for renin inhibitory activity. The investigation revealed that linear ...and sterically small side chain substituents are preferred in the S
3 sub-pocket for optimal renin inhibition. Polar groups in the S
3 sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with c
log
P’s
⩽
3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
A systematic investigation of the S
3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S
3 sub-pocket for optimal renin inhibition. Polar groups in the S
3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with c
log
P’s
⩽
3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
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Recently,
trans-disubstituted oxo-aryl-piperidines have been identified as small molecule nonpeptide renin inhibitors for the modulation of hypertension. Herein, we report on the ...discovery and preparation of a new class of novel
cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent in vitro renin inhibitors and also, possess in vivo antihypertensive activity in a double transgenic mouse model.
Ketopiperazine
2 was designed from a previously published analog. Compound
2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a ...hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound
2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme.
Ketopiperazine
2 was designed from a previously published analog. Compound
2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound
2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (
16).
Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(
π
+
σ) effect. A 3-pyridinyloxymethyl substituent ...was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(
π
+
σ) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
Both enantiomeric configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns.
We have found that both enantiomeric ...configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns. This enantiomeric flexibility is in contrast to a previously reported 3-alkoxymethyl-4-arylpiperidine scaffold.
The activated factor VII/tissue factor complex (FVIIa/TF) is known to play a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. A ...fluoropyridine-based series of FVIIa/TF inhibitors was discovered which utilized a diisopropylamino group for binding in the S2 and S3 binding pockets of the active site of the enzyme complex. In this series, an enhancement in binding affinity was observed by substitution at the 5-position of the hydroxybenzoic acid sidechain. An X-ray crystal structure indicates that amides at this position may increase inhibitor binding affinity through interactions with the S1′/S2′ pocket.
