Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors

Abstract

The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.

Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor

“…We have already found an attractive lead compound 1 with an IC 50 value of 4.6 nM against human plasma renin by our fragment-based (FBDD) and structure-based drug design (SBDD) efforts . The X-ray cocrystal structure of compound 1 bound to renin was examined in detail as the starting point for our next round of SBDD efforts (Figure ).…”

“…PK studies revealed that compound 1 has better oral bioavailability in rats than aliskiren ( 1 , 13.8%; aliskiren, 2.4%). − The reasons for this difference were thought to arise from improved physiochemical characteristics such as MW (414 and 552), topological polar surface area (TPSA) (82 and 146), and number of rotatable bonds (nRB) (9 and 20, respectively) which are known as important predictors for BA. , However, compound 1 possesses the furan moiety, which could potentially be oxidized by CYP to form toxic metabolites. , We sought to replace this moiety with metabolically stable substituent through chemical modification.…”

“…In the course of these modifications, the methoxypropylamino group was found as an alternative S3 sp site binder with a 10-fold decrease in renin inhibitory activity relative to the furfurylamine moiety ( 6 , hPRA IC 50 = 5.2 nM). The related methoxypropyloxy side chain is a well-known binding motif of the renin S3 sp site, present in aliskiren and in other renin inhibitors. ,, Next, optimization of the methoxycarbonyl moiety of compound 6 was conducted. While carbamoyl derivative 7 showed comparable renin inhibitory activity to 6 , morpholinocarbonyl derivative 8 exhibited potent inhibitory activity (hPRA IC 50 = 0.79 nM) as well as 5 , suggesting that occupation of the S1′ site would be effective for obtaining strong potency in hPRA assay, since introduction of the morpholinamide might induce the decrease of the human plasma protein binding.…”

Synthesis and Antifungal Activity Evaluation of Novel Substituted Pyrimidine‐5‐Carboxamides Bearing the Pyridine Moiety

“…In addition, among the pyrimidine derivatives, pyrimidine‐carboxamides represent a promising class of bioactive substances and have received much attention in the field of medicine. For example, 2‐thioxo‐1,2‐dihydro pyrimidine‐5‐carboxamides (I) have moderate antibacterial activity against Bacillus subtilis ; N ‐(piperidin‐3‐yl) pyrimidine‐5‐carboxamides (II) can be used as renin inhibitor; 1,2‐ dihydropyrimidine‐5‐carboxamide containing morpholine moiety (III) exhibits good antihypertensive activity; and di‐substituted amino pyrimidine‐5‐carboxamides (IV) synthesized by Liang behave as excellent BMX kinase inhibitors . Their structures are shown in Figure .…”

Synthesis and antinociceptive activities of some novel benzimidazole-piperidine derivatives

“…Among them, N -based heterocycles are especially important since many of the biologically active compounds such as alkaloids, glycosides, and hormones as well as some of the clinically used drugs carry N -containing heterocycles in their chemical structures. 1,2 As one of the N -based heterocycles, the piperidine ring system has been shown to possess various pharmacological effects such as antibacterial, antifungal, 3−5 anti-HIV, 6 antileishmanial, 7 anticancer, 8,9 renin inhibitory, 10 diuretic, and natriuretic 11 effects. Another N -containing heterocyclic structure, benzimidazole, is also known to have the ability to interact with biomolecules of living systems.…”